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Cited by 101T-cell and B-cell ImmunologyGenomics and Chromatin DynamicsDevelopmental Biology and Gene Regulation

Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development

Open access
Rothenberg, Ellen V., Hosokawa, Hiroyuki, Ungerbäck, Jonas·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.00228PMC PMC6391351
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Abstract

PU.1 is an ETS-family transcription factor that plays a broad range of roles in hematopoiesis. A direct regulator of myeloid, dendritic-cell, and B cell functional programs, and a well-known antagonist of terminal erythroid cell differentiation, it is also expressed in the earliest stages of T-cell development of each cohort of intrathymic pro-T cells. Its expression in this context appears to give T-cell precursors initial, transient access to myeloid and dendritic cell developmental competence and therefore to represent a source of antagonism or delay of T-cell lineage commitment. However, it has remained uncertain until recently why T-cell development is also intensely dependent upon PU.1. Here, we review recent work that sheds light on the molecular biology of PU.1 action across the genome in pro-T cells and identifies the genes that depend on PU.1 for their correct regulation. This work indicates modes of chromatin engagement, pioneering, and cofactor recruitment ("coregulator theft") by PU.1 as well as gene network interactions that not only affect specific target genes but also have system-wide regulatory consequences, amplifying the impact of PU.1 beyond its own direct binding targets. The genes directly regulated by PU.1 also suggest a far-reaching transformation of cell biology and signaling potential between the early stages of T-cell development when PU.1 is expressed and when it is silenced. These cell-biological functions can be important to distinguish fetal from adult T-cell development and have the potential to illuminate aspects of thymic function that have so far remained the most mysterious.

AI snapshot

Written from the paper’s full text.

TL;DR

PU.1 is transiently expressed in early pro-T cells, where it acts as a pioneer/cofactor-redistributing transcription factor that supports proliferation, delays commitment, and maintains a myeloid/dendritic-competence window constrained by Notch signaling. Its role is ontogenically scaled: largely dispensable in first-wave fetal T cells but important for later fetal and adult T-cell development.

Key findings

  • PU.1 binds >30,000 genomic sites in the earliest pro-T cells, declining to ~5,000 sites by T-lineage commitment; its motifs are highly enriched at chromatin sites that lose accessibility during commitment, and acute PU.1 deletion leaves many of these sites less open.
  • Within the T-cell pathway, PU.1 slows differentiation while supporting proliferation: PU.1-disrupted precursors underwent fewer cycles and a larger fraction progressed to DN3 over the same absolute time; high-confidence targets include activated genes such as Mef2c, Lmo2, Bcl11a, and Hhex, and repressed genes such as E2f2.
  • PU.1 directly regulates many signaling/cell-biology genes—cytokine receptors, chemokine receptors, tyrosine kinases, G-protein-coupled receptors, adhesion and cytoskeletal molecules—more than transcription factor genes, and can repress indirectly by “coregulator theft,” redistributing Runx1 and Satb1 away from other functional sites.
  • Ontogeny: first-wave fetal T cells tolerate ~5-fold reduced PU.1 almost unchanged, whereas later fetal hematopoietic stem/progenitor cells show severe T-cell defects; the PU.1 phase lasts >10 days in young adult thymocytes but may last only 1–2 days in many first-wave fetal thymocytes.

Methods

  • Review/synthesis of recent mouse T-cell development studies, mostly postnatal thymus or late fetal progenitors, using primary pro-T cells, OP9-DL1/DL4 stromal co-cultures, and the Scid.adh.2C2 pro-T-like cell line.
  • Gain- and loss-of-function perturbations: retroviral PU.1 overexpression, Cre-mediated Spi1 deletion, Cas9/sgRNA Spi1 disruption, and dominant-negative PU.1-ENG; readouts include ChIP-seq, ATAC-seq, transcriptome, proteomics, and GO/PANTHER pathway analyses.
  • High-confidence PU.1 target genes were defined as those showing reciprocal responses in gain- and loss-of-function perturbations within the DN2a–DN2b developmental interval.

Limitations

  • Stated: biochemical mechanisms of PU.1/Notch effects remain to be fully defined; PU.1 small-molecule inhibitors have not yet been tested in normal T-cell development; long PU.1 protein half-life and asynchronous deletion make loss-of-function effects weak at <2 days and confounded by developmental progression at later timepoints.
  • Stated: gain-of-function overexpression can inhibit Notch signaling and produce nonlinear, switch-like transdifferentiation, so some effects may be high-dose artifacts; Scid.adh.2C2 cells do not fully restore the ETP/DN2a chromatin landscape.
  • Evident: the review is largely based on mouse systems and in vitro cultures, which the authors note may lack normal thymic environmental molecules; PU.1-high early stages are rare and difficult to study directly in vivo.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fimmu.2019.00228

Cites

164 of 164 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

189 of 244 cited sources checked · 71 supported · 6 flagged · accuracy not yet measured

  • Premisecitation

    Even artificially high-level PU.1 can redirect differentiation to myeloid or dendritic fates only if Notch signaling is reduced.

    “Even artificially high-level PU.1 could only redirect the differentiation of the cells to myeloid or dendritic fates if Notch signaling were reduced (49, 50, 58).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [49] Franco, 2006, Notch/Delta signaling constrains reengineering of pro-T cells by PU.1 source

      The paper reports that Notch/Delta signaling prevents PU.1-driven myeloid diversion in T-lineage-specified pro-T cells (p. 1; Discussion, p. 5). But the Results (p. 4) show that earlier Thy-1-negative precursors generated myeloid-like cells after PU.1 expression even with Notch/Delta signaling. Thus the claim’s unqualified “only if” does not hold for all the cells studied. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [50] Laiosa, 2006, Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBPα and PU.1 transcription factors source
    • cites [58] Del Real, 2013, Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3 source

      The section ‘Pro-T cells with high levels of PU.1 protein are able to resist Mac1 upregulation in the presence of Notch signaling’ (page not provided) says Notch reduces the proportion of cells showing myeloid diversion, but Mac1 could still be induced at the highest PU.1 levels while Notch ligand was present. Thus, reduced Notch signaling was not an absolute requirement, contrary to ‘only if.’ (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    In primary pro-T cells and Scid.adh.2C2 cells, highly overexpressed PU.1 appears to inhibit Notch signaling, as measured by downregulation of Notch target genes and Notch1 itself.

    “In primary pro-T cells and Scid.adh.2C2 cells, highly overexpressed PU.1 appears to inhibit Notch signaling, as measured by downregulation of Notch target genes and even Notch1 itself.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [49] Franco, 2006, Notch/Delta signaling constrains reengineering of pro-T cells by PU.1 source

      In “Notch/Delta Signaling as a Specific Modifier of PU.1 Actions on Target” (p. 4), the paper says that Notch1 and Notch signal delivery were unaffected by PU.1 in Thy-1+ pro-T cells, and that two Notch target genes were virtually indifferent to PU.1. It does report PU.1 sensitivity of HES-1 and downregulation of Notch1 in a different, Thy-1-low subset, but those qualifications do not support the claimed inhibition in pro-T cells. The cited passages do not establish the claim for Scid.adh.2C2 cells. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [58] Del Real, 2013, Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3 source
  • Premisecitation

    The innate lymphoid cell developmental program appears to resemble the intrathymic T-cell program in many respects.

    “So far the innate lymphoid cell developmental program in particular appears to resemble the intrathymic T-cell program in many respects (154–157), enough to raise the question of what makes T-cell precursors wait to activate genes like Tcf7 and Gata3 until they reach the thymus.”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [154] Shih, 2016, Developmental acquisition of regulomes underlies innate lymphoid cell functionality source

      The Discussion section, “T cells and ILCs: Regulomes Converge following Infection” (page not provided), describes a “reasonably clear distinction” between ILC and T-cell development. The paper reports shared transcription factors and convergence of their regulomes after infection, but distinguishes those similarities from a resemblance between their developmental programs. (LLM, conf=0.83)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [155] Yu, 2016, Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [156] Cherrier, 2018, Innate lymphoid cell development: a T cell perspective source
    • cites [157] Harly, 2018, Development and differentiation of early innate lymphoid progenitors source
  • Premisecitation

    In myeloid, dendritic, and B lineage cells, PU.1 is a major contributor to positive regulation of genes that establish lineage-specific identity.

    “In myeloid, dendritic, and B lineage cells, PU.1 is a major contributor to the positive regulation of genes that establish lineage-specific identity (4, 17, 19).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [4] Friedman, 2007, Transcriptional control of granulocyte and monocyte development source
    • cites [17] Natoli, 2011, The genomic landscapes of inflammation source

      The section “The cis-regulatory repertoire of professional inflammatory cells” describes PU.1 as a lineage-determining factor that activates macrophage-specific enhancers and notes a distinct pattern of PU.1 binding in B cells. It does not establish the claimed positive regulation of lineage-identity genes across myeloid, dendritic, and B lineage cells; the evidence it discusses concerns enhancers, and it does not substantiate the dendritic-cell portion. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [19] Turkistany, 2011, The transcription factor PU.1 is a critical regulator of cellular communication in the immune system source
  • Premisecitation

    Precursors that give rise to committed T cells express PU.1 at RNA and protein levels for multiple cell divisions after thymic differentiation begins.

    “the precursors that give rise to committed T cells express PU.1 at both RNA and protein levels for multiple cell divisions after these cells begin to differentiate in the thymus (32, 33).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [32] Tydell, 2007, Molecular dissection of prethymic progenitor entry into the T lymphocyte developmental pathway source
    • cites [33] Yui, 2010, Fine-scale staging of T cell lineage commitment in adult mouse thymus source
  • May combine two claims. 80
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Premisecitation

    Small-molecule inhibitors of PU.1 have been discovered, some highly potent and specific at blocking PU.1 action in leukemia cells, but they have not yet been tested for effects on normal T-cell development.

    “A very intriguing new prospect for fast antagonism of PU.1 activity is the discovery of small-molecule inhibitors, some of which are highly potent and specific at blocking PU.1 action in leukemia cells; however, these have not yet been tested for effects on normal T-cell development (89).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [89] Antony-Debré, 2017, Pharmacological inhibition of the transcription factor PU.1 in leukemia source

      The Introduction supports the discovery of small-molecule PU.1 inhibitors that block PU.1 activity in AML cells. But the section “Inhibitors show on-target PU.1-inhibitory activity in AML cells” explicitly reports testing their effects on T-cell differentiation in OP9-Delta1 culture, contrary to the claim that they had not yet been tested for effects on normal T-cell development. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The best current candidates for this silencing activity include GATA-3, TCF-1 or LEF-1, and especially Runx1, probably working in a dose-dependent combination, although the mechanism through which they finally achieve the ability to repress PU.1 has not yet been reported.

    “The best current candidates for this silencing activity include GATA-3 (104, 105), TCF-1 or LEF-1 (37), and especially Runx1 (80, 150–152), probably working in a dose-dependent combination, although the mechanism through which they finally achieve the ability to repress PU.1 has not yet been reported.”
    Quote in the paperSubstantial claim4 of 7 sources checked
    • cites [104] Scripture-Adams, 2014, GATA-3 dose-dependent checkpoints in early T cell commitment source
    • cites [105] Taghon, 2007, Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3 source
    • cites [37] Rosenbauer, 2006, Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU source
    • cites [80] Hosokawa, 2018, Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding source

      The Results section on PU.1 association in primary DN cells says Runx1 becomes essential around the time PU.1 is downregulated, but does not say Runx1 silences PU.1. The Results and Discussion passages instead examine how PU.1 redirects Runx1 binding. Searches for Runx1-mediated PU.1 silencing and Spi1 downregulation found no passage supporting the proposed dose-dependent combination or the claim about its unknown mechanism. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [150] Huang, 2008, PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis source
    • cites [151] Hoogenkamp, 2009, Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [152] Zarnegar, 2010, Cell type-specific activation and repression of PU.1 by a complex of discrete, functionally specialized cis-regulatory elements source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PU.1 can bind as a collaboration-dependent partner with NF-κB or with C/EBPα/β or IRF4/8.

    “or as a collaboration-dependent partner in binding complexes, either with activation-dependent factors like NF-κB or with lineage-defining partners like C/EBPα (or β) or IRF4/8 (13–15)”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [13] Heinz, 2010, Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities source

      The section “PU.1 binds in the vicinity of other lineage-determining transcription factors” (page unavailable) reports nearby PU.1 and C/EBPα/β binding sites and describes a PU.1–IRF4/8 ternary complex. “Combinatorial interplay delineates stage-specific cistromes” (page unavailable) further reports reciprocal effects of PU.1 and C/EBPβ on binding. For NF-κB, however, the paper reports nearby motifs and its activation in TLR4 signaling, not a collaboration-dependent PU.1–NF-κB binding complex. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [14] Heinz, 2013, Effect of natural genetic variation on enhancer selection and function source

      In “Variation and collaborative LDTF binding” (page not provided), the paper reports that C/EBPα motif mutations can reduce nearby PU.1 binding, supporting collaboration between those factors. In “LDTF motif mutations affect NF-κB binding” (page not provided), it instead describes NF-κB binding at sites already bound by PU.1 and/or C/EBPα; it does not establish that PU.1 binding depends on NF-κB. The supplied passages and searches do not support the specified C/EBPβ or IRF4/8 partnerships. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [15] Ostuni, 2013, Latent enhancers activated by stimulation in differentiated cells source

      The Mechanistic Aspects section (p. 163) describes PU.1 recruitment as potentially dependent on cooperation with a stimulus-activated partner or constitutively expressed transcription factors. The Introduction also links PU.1-controlled enhancers with recruitment of stimulus-induced NF-κB. Our copy does not identify C/EBPα/β or IRF4/8 as PU.1 binding partners, and the proposed cooperative mechanisms are not established for those named factors. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PU.1 can work in an all-or-none gene network switch through mutual antagonism with GATA-1.

    “PU.1 can work in an all-or-none gene network switch through mutual antagonism with GATA-1 (20–24)”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [20] Rekhtman, 1999, Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells source

      The section “Mechanism of PU.1-mediated block to differentiation in erythroleukemia” (page unavailable) says PU.1 and GATA-1 can antagonize each other’s actions and suggests their relative levels could regulate lineage commitment. The paper does not establish an all-or-none gene-network switch; its lineage-commitment proposal is conditional. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [21] Zhang, 1999, Negative cross-talk between hematopoietic regulators: GATA proteins repress PU source

      The Results (page unavailable) show reciprocal inhibition: GATA-1 represses PU.1 transactivation, and PU.1 inhibits GATA-1 activation in reporter assays. The Discussion links this negative regulation to hematopoietic differentiation, but the paper does not establish an all-or-none gene-network switch. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [22] GATA-1 interacts with the myeloid PU.1 transcription factor and represses PU.1-dependent transcription254351 NerlovC QuerfurthE KulessaH GrafT 10753833Blood952000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [23] PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding264148 ZhangP ZhangX IwamaA YuC SmithKA MuellerBU 11023493Blood962000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [24] Stopka, 2005, PU.1 inhibits the erythroid program by binding to GATA-1 on DNA and creating a repressive chromatin structure source

  • May combine two claims.

    Premisecitation

    The transition at commitment includes general downregulation of phase 1 genes and major reorganization of active chromatin and chromatin interactions genome-wide.

    “This is part of a general downregulation of stem/progenitor associated regulatory genes (“phase 1 genes”) (34, 43) and a major reorganization of active chromatin and chromatin interactions, genome-wide, that occurs during this transition (44).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [34] Rothenberg, 2016, Forging T-Lymphocyte identity: intersecting networks of transcriptional control source
    • cites [43] Rothenberg, 2010, Multilayered specification of the T-cell lineage fate source

      Citation (44) is attached to the claim of genome-wide reorganization of active chromatin and chromatin interactions. Our copy discusses downregulation of stem/progenitor-associated genes in “Unleashing the expression of T-cell identity by negative regulation?” and local chromatin opening at TCR loci in “Emergence of T-cell identity,” but neither establishes the cited genome-wide reorganization. Searches for chromatin reorganization and chromatin interactions found no passage addressing it; page numbers were unavailable. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [44] Hu, 2018, Transformation of accessible chromatin and 3D nucleome underlies lineage commitment of early T cells source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PU.1 binds DNA typically at (A/G)AGGAAGTG motifs.

    “typically (A/G)AGGAAGTG motifs [e.g., (10, 11)]”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [10] Poon, 2004, A thermodynamic basis of DNA sequence selectivity by the ETS domain of murine PU source
    • cites [11] Pham, 2013, Mechanisms of in vivo binding site selection of the hematopoietic master transcription factor PU.1 source

  • May combine two claims.

    Premisecitation

    Re-expression of PU.1 after T-cell commitment turns on myeloid genes and can transform later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells.

    “re-expression of PU.1 after T-cell commitment turns on myeloid genes and readily transforms later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells (46–50).”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [46] Anderson, 2002, Constitutive expression of PU.1 in fetal hematopoietic progenitors blocks T cell development at the pro-T cell stage source
    • cites [47] Dionne, 2005, Subversion of T lineage commitment by PU.1 in a clonal cell line system source

      The Results report that PU.1 induced myeloid-associated genes in a pro-T cell line, and the section on diverted gene expression reports that committed DN3 thymocytes acquired Mac1 expression and non-lymphoid morphology after PU.1 was restored. The paper describes this as diversion to a myeloid-like phenotype, not demonstrated transformation of later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [48] Lefebvre, 2005, Enforced expression of Spi-B reverses T lineage commitment and blocks β-selection source

      The organ-culture results (page not available) report that PU.1 expression induced a dendritic-cell marker and diverted thymocytes toward that lineage, but identify the affected DN1–DN2 cells as not yet committed to the T-cell lineage. The Discussion attributes diversion of committed DN3 cells to Spi-B, not PU.1. The paper does not establish that PU.1 re-expression in later committed pro-T cells activates myeloid genes or produces macrophages or promyelocytic-like cells. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [49] Franco, 2006, Notch/Delta signaling constrains reengineering of pro-T cells by PU.1 source

      In the Results (p. 4), PU.1-transduced pro-T and pre-T cells activate a broad spectrum of myeloid genes and can acquire myeloid markers. The paper does not establish that later committed cells readily become each of the three named cell types: it describes myeloid-like cells, cites earlier work for a dendritic-cell fate (p. 1), and reports that Notch/Delta signaling blocks diversion in the specified cells (p. 4). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [50] Laiosa, 2006, Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBPα and PU.1 transcription factors source

      The Discussion (page not available) says enforced PU.1 expression in committed pre-T cells induced cells resembling myeloid dendritic cells, and that PU.1 induces dendritic genes and a subset of myeloid genes. It distinguishes this from macrophage formation, which it attributes to C/EBPα and C/EBPβ; the cited passages do not report PU.1 producing promyelocytic-like cells. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Conditional deletion of Spi1 in T-lineage cells after DN2 has only modest effects on T cells as a whole, limited to selective reduction of IL-9-producing T-cells and some loss of restraint on γδ T cells and Tfh activity.

    “if Spi1 is conditionally deleted in T-lineage cells only after the cells have passed the DN2 stage, there are very modest effects on T cells as a whole, apparently limited to selective reduction of IL-9-producing T-cells (74), and some loss of restraint on γδ T cells and T follicular helper cell activity (75, 76).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [74] Chang, 2010, The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation source

      The Results (‘PU.1 promotes the development of IL-9–secreting T cells’; page unavailable) report reduced IL-9 in PU.1-deficient T-cell cultures, supporting the finding attached to citation 74. But the Results (‘TH9 cells and allergic inflammation’) also report reduced production of the chemokines Ccl17 and Ccl22 from those T cells, so the effects are not shown to be limited to IL-9-producing cells. The γδ T-cell and Tfh findings are attached to other citations, not this one. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [75] Jabeen, 2011, The transcription factor PU.1 regulates γδ T cell homeostasis source

      The Results report that Lck-Cre deletion of Sfpi1 leaves αβ T-cell profiles largely unchanged but increases γδ T-cell numbers, supporting the portion attributed to this paper (Results, ‘γδ T cell numbers are expanded in the absence of PU.1’; page unavailable). The Discussion places deletion after Sfpi1 expression declines between DN1 and DN2, but does not establish that deletion occurs only after cells have passed DN2. The IL-9 and Tfh portions carry other citations in the citing sentence. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [76] Awe, 2015, PU.1 Expression in T follicular helper cells limits CD40L-dependent germinal center B Cell development source

  • May combine two claims.

    Interpretationcitation

    PU.1 is important within the T-cell program as well as before thymic entry.

    “PU.1 is indeed important within the T-cell program as well as before thymic entry, as shown by using in vitro differentiation to provide conditions where PU.1 could be removed acutely in a synchronized cohort of precursors and the fates of the cells could be monitored immediately afterwards.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source
    • cites [80] Hosokawa, 2018, Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding source

      The Results section on endogenous PU.1 in pro-T cells reports that acute disruption during in vitro differentiation altered proliferation, developmental progression, and gene expression, supporting its importance within the T-cell program. The paper does not establish PU.1’s importance before thymic entry; its fetal-liver precursors were used to initiate cultures, but the reported disruption occurred when cells were at the DN1 stage. The cited Results passage also assesses cells four days after disruption, rather than immediately afterward. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ETP and DN2 cells can generate myeloid cells if removed from the thymus, whereas pro-T cells past PU.1 expression (DN3 or later) do not make myeloid cells under these conditions.

    “Whereas ETP and DN2 cells can generate myeloid cells if removed from the thymus, pro-T cells that have differentiated past the stage of PU.1 expression in the thymus (i.e., from the DN2 stage to the DN3 stage or later) do not make myeloid cells under these conditions”
    Quote in the paperSubstantial claim5 of 9 sources checked
    • cites [33] Yui, 2010, Fine-scale staging of T cell lineage commitment in adult mouse thymus source

      The Introduction says DN2 cells retain possible myeloid potential while DN3 cells are committed to the T lineage. The Results section on DC and NK potential reports that ETP and DN2a cells produce alternative lineages without Notch signaling, whereas DN2b and DN3a cells produce few, if any, DCs or NK cells. It does not directly test myeloid production at those stages, and the gene-expression Results place the first decline in PU.1 at DN2b, before DN3. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [40] Bell, 2008, The earliest thymic progenitors for T cells possess myeloid lineage potential source
    • cites [41] Wada, 2008, Adult T-cell progenitors retain myeloid potential source
    • cites [51] Wu, 1996, Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny source

      In ‘Development of Lymphoid and Myeloid Cells from Intrathymic Precursors’ (pp. 905–906), the authors report that after intravenous transfer, the early low-CD4 precursors produced no discrete myeloid population and the CD44+CD25+ pro-T precursors produced myeloid cells only at background levels. They also report that the later CD44−CD25+ pre-T population could not form myeloid cells. Thus the later-stage finding is supported, but the claimed myeloid capacity of the earlier cells under these conditions is contrary to the reported results; the copy does not establish a PU.1-defined boundary. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [52] Lee, 2001, Generation of macrophages from early T progenitors in vitro source

      The Results section ('Both Pro-T1 and T2 cells can generate macrophages'; page not supplied) reports that pro-T1 and pro-T2 cells generated macrophages in culture, whereas pro-T3 and pro-T4 cells did not under those conditions. The paper does not establish the claim's PU.1-expression boundary or test stages later than pro-T4. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [53] King, 2002, Lineage infidelity in myeloid cells with TCR gene rearrangement: a latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling source

      The Results (page not specified) show that isolated proT1 and proT2 cells generated granulocyte/macrophage cells, whereas TN3 and TN4 cells did not, in the tested cultures. But proT2 myeloid development required ectopic IL-2 receptor expression and added human IL-2; removal from the thymus alone was not sufficient. The cited passages also do not establish PU.1 expression as the reason for the DN2-to-DN3 boundary. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [54] Balciunaite, 2005, The earliest subpopulation of mouse thymocytes contains potent T, significant macrophage, and natural killer cell but no B-lymphocyte potential source
    • cites [55] Ikawa, 2010, An essential developmental checkpoint for production of the T cell lineage source
    • cites [56] Luc, 2012, The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential source

      The Results section on ETPs and bone-marrow progenitors reports that DN2 cells retain T-cell and granulocyte–monocyte potential, while DN3 cells are the first T-cell-restricted progenitors (page unavailable). The Results on neonatal ETPs demonstrate myeloid potential in cultures outside the thymus. Our copy does not establish that the DN2-to-DN3 change coincides with the end of PU.1 expression or directly test DN2 and DN3 cells under the same removal conditions. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Effects on target gene regulation appear very weak at timepoints up to 2 days after PU.1 deletion, despite reduced cell yields from knockout cells showing that PU.1 is biologically important.

    “the effects on target gene regulation appear very weak at timepoints up to 2 days after PU.1 deletion, despite the fact that the reduced cell yields from the knockout cells show that PU.1 is biologically important (79).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

  • May combine two claims.

    Premisecitation

    PU.1 can upregulate progenitor-associated genes Bcl11a, Lmo2, Mef2c, and Hhex above their normal levels in DN2a and DN2b primary cells, whereas PU.1-ENG can downregulate them.

    “whereas PU.1 itself can upregulate progenitor-associated genes Bcl11a, Lmo2, Mef2c, and Hhex above their normal levels in DN2a and DN2b primary cells, PU.1-ENG can downregulate them (79).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

      In Results, under “Selective roles for PU.1 in the progenitor-associated regulatory gene network” (page unavailable), the paper reports that added wild-type PU.1 up-regulated Bcl11a, Lmo2, and Mef2c, consistent with effects of PU.1-Eng. It does not name Hhex among those genes, so the claim about all four is not fully supported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductcitation

    In the Cas9-dependent acute deletion system, deletion and clearance of PU.1 protein require analysis more than 2 days after introduction of guide RNAs, and the continuing developmental progression of both knockout samples and controls needs to be taken into account in interpreting results.

    “However, deletion and clearance of PU.1 protein in this system still require analysis >2 days after introduction of the guide RNAs (80, 85), and the continuing developmental progression of both knockout samples and controls needs to be taken into account in interpreting the results.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [80] Hosokawa, 2018, Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Gene expression profiles of cells losing CD25 and upregulating CD11b are radically transformed from newly-committed pro-T cells within 2 days after transduction, with widespread repression of T-lineage-affiliated TF genes and Notch target genes and upregulation of multiple Cebp and Irf family TF genes.

    “The gene expression profiles of cells losing CD25 and upregulating CD11b are radically transformed from the state of newly-committed pro-T cells within 2 days after transduction, with widespread repression of T-lineage-affiliated transcription factor genes and Notch target genes as well as upregulation of multiple Cebp and Irf family transcription factor genes (Figure 4) (85).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The PU.1-ENG construct has been useful to reveal quick impacts on expression of positively regulated PU.1 target genes, many of which have been confirmed later by other approaches.

    “This construct has been useful to reveal quick impacts on expression of positively regulated PU.1 target genes, many of which have been confirmed later by other approaches (85).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

      The Results section on PU.1’s non-DNA-binding domains (page unavailable) reports that PU1ENGHA represses several genes positively regulated by full-length PU.1. The Discussion (page unavailable) says that gain- and loss-of-function approaches defined a core group of positive PU.1 targets. Our copy does not establish that the PU.1-ENG construct revealed quick expression impacts or that many targets identified specifically through it were later confirmed by other approaches. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Sites occupied by exogenous PU.1 in Scid.adh.2C2 overlap highly with endogenous PU.1 sites in normal pro-T cells, but the match is not complete.

    “The sites occupied by exogenous PU.1 in Scid.adh.2C2 cells overlap highly with the sites occupied by endogenous PU.1 in normal pro-T cells, but the match is by no means complete (85).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

  • May combine two claims.

    Premisecitation

    Target genes stimulated by PU.1 include both pro-proliferative and G1-prolonging cell cycle effectors, whereas some important proliferative genes are repressed when PU.1 levels are high.

    “The target genes stimulated by PU.1 include both pro-proliferative and G1-prolonging cell cycle effectors, whereas some important proliferative genes are repressed when PU.1 levels are high (82, 83).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [82] Kueh, 2013, Positive feedback between PU.1 and the cell cycle controls myeloid differentiation source

      In the passage on regulatory gene expression (indexed as Abstract; page unavailable), PU.1 transduction reduced Cyclin D2, Cdc25a, Myb, and Myc, supporting the repression of proliferative genes. The paper says PU.1 promotes growth in some progenitors and notes that p21 and Gfi1 are up-regulated by PU.1 in stem cells, but it does not establish here that PU.1 stimulates both pro-proliferative and G1-prolonging target genes. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [83] Staber, 2013, Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells source

      The Results section, “PU.1 Transcriptionally Induces Cell-Cycle Inhibitors and Represses Cell-Cycle Activators” (page unavailable), supports PU.1 stimulation of cell-cycle inhibitors and repression of proliferative genes. It does not support the additional claim that PU.1 stimulates pro-proliferative cell-cycle effectors; the activators examined here were repressed. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Even with PU.1 transduction, Scid.adh.2C2 cells do not restore the full chromatin accessibility landscape of ETP and DN2a pro-T cells and reactivate little of the normal context program.

    “Even with PU.1 transduction, Scid.adh.2C2 cells do not restore the full chromatin accessibility landscape of ETP and DN2a stage pro-T cells, and despite detectable upregulation of a few other early pro-T cell genes (e.g., Bcl11a and Lyl1), the transduced cells as a whole reactivate little of the program that forms the normal context for endogenous PU.1 activity in pro-T cells (58, 79, 85).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [58] Del Real, 2013, Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3 source

      The section on the Scid.adh.2C2 cell line describes it as DN3-like and reports that PU.1 transduction upregulated Mac1 in only a fraction of cells. The paper also reports PU.1-dependent repression of T-cell genes, which is consistent with an incomplete early pro-T-cell response. But our copy does not compare these cells’ chromatin accessibility with ETP or DN2a cells, or establish how much of the normal early pro-T-cell program they reactivate. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

      The Results section on PU.1-Eng specificity reports that wild-type PU.1 transduction of Adh.2C2 cells causes myeloid diversion and represses many T-cell genes. It does not assess whether those cells restore ETP/DN2a chromatin accessibility or how much of the early pro-T-cell program they reactivate. Searches for chromatin accessibility and early-program reactivation in Adh.2C2 cells did not find a passage establishing either point. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

      The Results section on pioneering in DN3-like cells (page unavailable) shows that PU.1 transduction opens previously closed sites and activates some linked genes. The paper identifies Scid.adh.2C2 cells as DN3-like, but the passages do not establish that transduction fails to restore the full ETP/DN2a accessibility landscape or that the cells reactivate little of the normal early pro-T-cell program. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PU.1 protein is highly stable, which can magnify its impact on cells despite modest RNA transcript levels.

    “although the RNA transcript levels are modest in absolute terms, the impact of PU.1 on the cells can be magnified by the high stability of PU.1 protein (82).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [82] Kueh, 2013, Positive feedback between PU.1 and the cell cycle controls myeloid differentiation source

      The passage discussing PU.1 removal (Fig. 1E; page unavailable) says its protein half-life is substantially longer than the progenitor cell cycle. The passages discussing cell-cycle lengthening (Figs. 1F–H and 3C–D; page unavailable) show that PU.1 can accumulate to higher levels without increased synthesis, supporting the proposed magnifying effect. Our copy does not establish that PU.1 RNA transcript levels are modest in absolute terms. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Scid.adh.2C2 cells respond in an all-or-none way to forced PU.1, coordinately upregulating myeloid/dendritic genes and downregulating T-cell genes in a discrete fraction increasing with PU.1 levels.

    “They respond in an all-or-none way to forced expression of PU.1, coordinately upregulating myeloid- or dendritic-cell associated genes and downregulating T-cell genes in a discrete fraction of the cells that increases with increasing levels of PU.1 (47, 58)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [47] Dionne, 2005, Subversion of T lineage commitment by PU.1 in a clonal cell line system source
    • cites [58] Del Real, 2013, Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3 source

      The section on Scid.adh.2C2 cells reports an all-or-none response to forced PU.1, with Mac1 upregulated in a fraction of cells; the gene-expression sections link diversion to repression of T-cell genes and induction of myeloid markers (page unavailable in our copy). However, the passage relating PU.1 protein levels to the fraction of Mac1-positive cells concerns fetal thymocytes, not Scid.adh.2C2 cells. This source therefore does not establish that the responding fraction of Scid.adh.2C2 cells increases with PU.1 level. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The PU.1-ENG obligate repressor should affect PU.1 positive regulation targets in the opposite direction from wildtype PU.1, and in theory should affect PU.1 negative regulation targets in the same direction.

    “The obligate repressor should affect PU.1 positive regulation targets in the opposite direction from wildtype PU.1, and in theory should affect PU.1 negative regulation targets in the same direction, an “algebraic sign” distinction that could be used in principle to dissect indirect effects as well (79).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

      The Results section describes PU.1-Eng as an obligate repressor that antagonizes PU.1-dependent activation, supporting the predicted opposite effect on positively regulated targets. In “Negative regulation of T-cell development by PU.1 is indirect” (page unavailable), it predicts the same effect as wild-type PU.1 only for directly repressed genes; genes repressed indirectly through an intermediate repressor would instead be up-regulated by PU.1-Eng. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PU.1-ENG has some spurious effects and cannot access closed chromatin sites as well as full-length PU.1.

    “However, PU.1-ENG also has some spurious effects and cannot access closed chromatin sites as well as full-length PU.1 (79, 85).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

      The Discussion (page unavailable) acknowledges caveats of forced PU.1-Eng expression and reports that some genes bound by endogenous PU.1 were unaffected by PU.1-Eng. The Results section on specificity (page unavailable) tests for side effects but finds the construct selective. Neither passage establishes that PU.1-Eng has spurious effects or that its weaker response at some sites is due to an inability to access closed chromatin relative to full-length PU.1. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

      The Results section on PU.1’s non-DNA-binding domains (page unavailable) reports that PU1ENGHA bound comparably to full-length PU.1 at open sites but much less at closed sites. The paper describes PU1ENGHA as primarily repressing targets rather than activating them, but the passages do not establish that it has spurious effects. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Scid.adh.2C2 cells are similar to developmentally arrested committed DN3 pro-T cells and lack endogenous PU.1.

    “These cells were a subclone derived from the Scid.adh cell line (87) and are similar to developmentally arrested versions of committed DN3 pro-T cells, lacking any expression of endogenous PU.1 (47).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [47] Dionne, 2005, Subversion of T lineage commitment by PU.1 in a clonal cell line system source

      The Introduction identifies adh.2C2 as a SCID.adh subclone with a DN3-like phenotype, and the Results describe the SCID.adh cells as arrested at a developmental stage. The Introduction says the subclone has ‘little if any’ endogenous PU.1 expression; the DN3-comparison section says it does not express PU.1 significantly. Those passages support very low expression, but not the categorical claim that it lacks any expression. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The long half-life of PU.1 protein can mask some loss effects at time points less than 2 days after deletion, while development can proceed to new stages if time windows are extended.

    “One problem is that the long half-life of PU.1 protein (82) can mask some loss effects at time points <2 days after deletion, while development of the pro-T cells can proceed to new stages if time windows are extended further.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [82] Kueh, 2013, Positive feedback between PU.1 and the cell cycle controls myeloid differentiation source

  • May combine two claims.

    Findingcitation

    In pro-T cells forced to express PU.1, those that make the lineage jump (lose CD25, gain CD11b) not only silence Notch1 but also activate myeloid regulatory genes.

    “Second, in pro-T cells forced to express PU.1, those that make the lineage jump (i.e. lose CD25, gain CD11b) not only silence Notch1 but also activate myeloid regulatory genes (85).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

      The Results section on PU.1 pioneering in DN3-like cells (page unavailable) reports that induced PU.1 lowers CD25 and later raises CD11b. The Discussion reports positive regulation of genes by PU.1 in pro-T cells, but our copy does not establish that the CD25-losing, CD11b-gaining cells silence Notch1 or activate myeloid regulatory genes specifically. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PU.1 occupancy of genomic sites declines as development proceeds, but is still detectable through T-lineage commitment at approximately 5,000 sites before disappearing.

    “Although PU.1 occupancy of genomic sites declines as development proceeds, PU.1 occupancy is still detectable through T-lineage commitment at ~5,000 sites before disappearing (84).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [84] Zhang, 2012, Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity source

      The Results section, “Early T-cell specific sites for PU.1: a positive role” (page unavailable), reports reduced PU.1 binding intensity in FLDN2b cells at T-lineage commitment and absence of PU.1 in later DP cells. It does not report approximately 5,000 occupied sites at commitment; the site count it gives is approximately 34,000 in DN T cells. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Approximately half of PU.1 occupancy sites in early pro-T cells are relatively inaccessible by ATAC-seq, showing that PU.1 binding can occur without opening chromatin.

    “However, approximately half of the PU.1 occupancy sites in early pro-T cells appear to be relatively “inaccessible” in chromatin by the criterion of ATAC-seq at the stages when PU.1 is seen to be binding there, showing that PU.1 binding can occur without opening the chromatin.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

  • May combine two claims.

    Findingcitation

    Full-length PU.1 binds closed sites nearly as well as open sites, whereas the isolated PU.1 DNA binding domain binds open sites as well as full-length but selectively fails to bind at closed sites.

    “Full-length PU.1 binds closed sites nearly as well as open sites, whereas the isolated PU.1 DNA binding domain binds open sites as well as full-length but selectively fails to bind at closed sites (85) (Figure 6).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

      In Results (‘PU.1 requires its non-DNA-binding domains to occupy sites in closed chromatin,’ Fig. 5E–F), the truncated constructs match full-length PU.1 at open sites but bind substantially less at closed sites. The claim that full-length PU.1 binds closed sites ‘nearly as well’ as open sites overstates the finding: the Results describe an affinity cost for entering closed chromatin. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The PU.1-ENG obligate repressor downregulated genes that are positive regulatory targets of wildtype PU.1, but upregulated many genes that wildtype PU.1 represses, inconsistent with a direct repression mechanism.

    “while the obligate repressor downregulated genes that are positive regulatory targets of wildtype PU.1, it actually upregulated many genes that wildtype PU.1 represses, completely inconsistent with a direct repression mechanism (79).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

  • May combine two claims.

    Premisecitation

    PU.1 has chromatin opening activity in B cells, can eject nucleosomes in macrophage lines, and causes rapid increases in ATAC accessibility at sites it occupies when introduced into Scid.adh.2C2 cells.

    “This is consistent with PU.1's activity as a site-specific chromatin opening factor in B cells (96, 97), with the ability of PU.1 to eject nucleosomes from sites where it binds in macrophage lines (12), and with its ability to cause rapid increases in ATAC accessibility at the sites it occupies when introduced into Scid.adh.2C2 cells (85).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [96] Nikolajczyk, 1999, ETS protein-dependent accessibility changes at the immunoglobulin æ heavy chain enhancer source
    • cites [97] Marecki, 2004, PU.1 as a chromatin accessibility factor for immunoglobulin genes source
    • cites [12] Barozzi, 2014, Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers source

      The Results section ('Selective masking of engaged Pu.1 sites by nucleosomes'; page unavailable) reports removal of a centrally positioned nucleosome at some Pu.1-bound sites, but only partial displacement and repositioning at others. The Introduction identifies the study system as primary mouse macrophages, not macrophage cell lines. The B-cell and Scid.adh.2C2 statements have separate citations and are not assessed here. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PU.1 acts as a repressor by direct recruitment of Dnmt3b.

    “It is also reported to act as a repressor by direct recruitment of Dnmt3b (102).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [102] de la Rica, 2013, PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation source

  • May combine two claims.

    Premisecitation

    At high levels, PU.1 blocks DNA binding by GATA-1; at lower levels it antagonizes GATA-1-mediated transactivation by forming complexes with it that recruit Rb through the PU.1 acidic transactivation domain.

    “At high levels, PU.1 has been found to block DNA binding by GATA-1 (23), while at lower levels it is reported to antagonize GATA-1-mediated transactivation by forming complexes with it that recruit Rb through the PU.1 acidic transactivation domain (101).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [23] PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding264148 ZhangP ZhangX IwamaA YuC SmithKA MuellerBU 11023493Blood962000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [101] Rekhtman, 2003, PU.1 and pRB interact and cooperate to repress GATA-1 and block erythroid differentiation source

  • May combine two claims.

    Premisecitation

    In pro-T cells, a key positive regulatory partner of PU.1 is Runx1, which has long been known to interact with PU.1 to form a functional complex at myeloid positive regulatory target sites.

    “For PU.1 in pro-T cells, IRF and C/EBP family partners are mostly not available, but a key positive regulatory partner is Runx1 (previously known as AML1 or CBFα2), which has long been known to interact with PU.1 (and C/EBPα) to form a functional complex at its myeloid positive regulatory target sites (9, 112, 113).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [9] Imperato, 2015, The RUNX1-PU.1 axis in the control of hematopoiesis source

      The ‘Developmental-stage-specific RUNX1 and PU.1 function’ section says RUNX1 and PU.1 form a synergistic complex in myeloid cells that regulates lineage-specific genes. The ‘RUNX1 and PU.1 in T and B-cells’ section discusses each factor’s role in early T-cell development but does not establish that RUNX1 is a key positive partner of PU.1 in pro-T cells. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [112] Petrovick, 1998, Multiple functional domains of AML1: PU

      Not checked in the free run.

    • cites [113] Leddin, 2011, Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells source

      The section on regulation of PU.1 in mice says RUNX1 activates the PU.1 upstream regulatory element early in development, supporting a positive regulatory role. It does not establish that Runx1 is a key PU.1 partner in pro-T cells or that the two form a functional complex at myeloid target sites; the paper examines regulation at the PU.1 locus in B and myeloid cells. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    PU.1 is functionally important for the open status of these chromatin sites in early stages; many sites do not remain open if PU.1 is removed acutely from primary pro-T cells by Cas9-mediated deletion.

    “PU.1 itself is functionally important for the open status of these chromatin sites in the early stages, for many of these sites in fact do not remain as open if the PU.1 is removed acutely from primary pro-T cells by Cas9-mediated deletion (85).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [85] Ungerbäck, 2018, Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1) source

  • May combine two claims.

    Premisecitation

    Egr2 can collaborate with PU.1 in positive regulation when co-bound with it, but has also been implicated as a PU.1-stimulated repressor of the mir17~92 complex.

    “Egr2, for example, can collaborate with PU.1 in positive regulation when co-bound with it (106), but has also been implicated as a PU.1-stimulated repressor of the mir17~92 complex (107).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [106] Krysinska, 2007, A two-step, PU.1 dependent, mechanism for developmentally regulated chromatin remodelling and transcription of the c-fms gene source
    • cites [107] Pospisil, 2011, Epigenetic silencing of the oncogenic miR-17-92 cluster during PU.1-directed macrophage differentiation source

  • May combine two claims.

    Premisecitation

    Runx1 is depleted from alternative sites when PU.1 is expressed, and the sites it abandons are themselves highly functional sites.

    “However, the aspect of this redistribution that is most notable is that Runx1 is depleted in the process from alternative sites, and the sites that it abandons are themselves highly functional sites.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [80] Hosokawa, 2018, Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding source

  • May combine two claims.

    Premisecitation

    PU.1 is not uniquely responsible for the Phase 1 gene expression pattern; other Phase 1 genes are either unaffected or moderately inhibited by PU.1.

    “PU.1 is not uniquely responsible for the Phase 1 gene expression pattern, however, for other Phase 1 genes are either unaffected or moderately inhibited by PU.1, as discussed elsewhere (79, 123).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

      The Discussion (page unavailable) rules out PU.1 as a global positive regulator of Phase 1 genes and says it blunts expression of one group. The Results section on the progenitor-associated regulatory gene network (page unavailable) likewise reports repression of several Phase 1 genes, but the cited passages do not establish that other Phase 1 genes are unaffected or that the inhibition is moderate. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [123] Longabaugh, 2017, Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network source

      In “Explaining Bcl11b Impact on Development” (page unavailable), the paper finds that PU.1-dependent genes form a subset of early-expressed genes and that PU.1 and Bcl11b provide mostly orthogonal inputs. It also reports weak PU.1 repression of Kit, but does not establish that the other Phase 1 genes are generally unaffected or moderately inhibited by PU.1. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PU.1 does not appear to bind, even transiently, at the sites from which Runx1 is lost; Runx1 is competitively redistributed, but is not displaced.

    “First, PU.1 does not appear to bind, even transiently, at the sites from which Runx1 is lost: Runx1 is competitively redistributed, but is not displaced.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [80] Hosokawa, 2018, Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding source

  • May combine two claims.

    Interpretationcitation

    Additional factors probably collaborate with PU.1 to fine-tune the responses of Mef2c and Lmo2, because they are already declining by the end of ETP stage, multiple cell cycles before DN2b stage when PU.1 itself declines.

    “Additional factors also probably collaborate with PU.1 to fine-tune the responses of Mef2c and Lmo2, for they are already declining by the end of ETP stage, multiple cell cycles before DN2b stage when PU.1 itself declines (65, 67, 84, 121, 124) (Figure 8A).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [65] Yui, 2014, Developmental gene networks: a triathlon on the course to T cell identity source

      The ‘Transition to phase 2’ section says Spi1 (PU.1) is turned off as cells progress through DN2b, and ‘Checkpoint failure and T-cell leukemias’ says some progenitor genes terminate expression within the ETP stage. Neither passage identifies Mef2c and Lmo2 as declining by the end of ETP or says that other factors collaborate with PU.1 to fine-tune their responses. The paper describes several cell cycles before DN2b in relation to TCF-1 and GATA-3 activation, not the proposed decline of those two genes. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [67] Manesso, 2013, Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence source

      The Discussion describes division-linked changes in DN1 cells’ competence to progress to DN2, but does not address Mef2c or Lmo2 expression or PU.1’s decline. Searches for those factors and the claimed ETP-to-DN2b timing found no passage in our copy that verifies the comparison. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [84] Zhang, 2012, Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity source

      The Results section on transcription-factor expression dynamics reports that Mef2c, Lmo2, and Sfpi1 (PU.1) decrease between FLDN1 and FLDN2b. The Results section on early T-cell-specific PU.1 sites says PU.1 is markedly downregulated at DN2b, and the binding-dynamics section suggests PU.1 can act through combinations of binding complexes. Our copy does not establish that Mef2c and Lmo2 begin declining by the end of ETP, multiple cell cycles before PU.1, or that other factors specifically collaborate with PU.1 to regulate those two genes. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Cells in these stages are hard to visualize in the intact thymus, as only a few cells per day enter the thymic antechamber, then migrate slowly through the cortex, dispersing among more advanced T-cell precursors.

    “However, cells in these stages are hard to visualize in the intact thymus, as only a few cells per day are granted regulated entry into the thymic antechamber (127), then migrate slowly through the cortex, dispersing among a vast excess of more advanced T-cell precursors, as they begin to differentiate toward commitment (128).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [127] Zietara, 2015, Multicongenic fate mapping quantification of dynamics of thymus colonization source

      The Abstract (page unavailable) says that low numbers of progenitors enter the thymus, making them difficult to characterize, and describes thymus colonization as tightly controlled. Its estimate of 10–200 cells per day, however, is explicitly for irradiated adult thymi; it does not establish that daily rate for the intact, unirradiated thymus. The later migration through the cortex is attached to citation (128), not this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [128] Lind, 2001, Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development source

      The Discussion (page unavailable) reports that precursors migrate outward across the cortex while progressing through defined developmental stages, supporting the migration-and-differentiation portion attributed to this paper. It describes the stages as concentrated in distinct cortical regions, however, and does not establish that the cells disperse among a vast excess of more advanced precursors. The separate claim about a few cells entering per day is attached to citation 127, not this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PU.1 activity probably extends for over 10 days for thymocytes in young adult mice, where it is crucial for successful T-cell generation.

    “It probably extends for over 10 days for the thymocytes in young adult mice (153), where it is crucial for successful T-cell generation (2, 147).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [153] Porritt, 2003, Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice source

      The Results and Discussion (page unavailable) report that thymic progenitors take about 15 days to reach the double-positive stage, supporting a developmental interval longer than 10 days. The paper does not establish that PU.1 remains active throughout that interval. The statement about PU.1 being crucial for T-cell generation is attached to other citations, not this one. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [2] Dakic, 2005, PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis source

      The Results (‘PU.1-deficient stem cells do not generate lymphoid progeny’; page unavailable) report that PU.1-deficient progenitors were essentially unable to contribute to T-cell production, supporting its importance for T-cell generation. The paper does not establish that PU.1 remains active in thymocytes for over 10 days; the Results (‘Generation and validation of a PU.1 conditional allele’) instead state that most thymocytes do not express it. Its 10–14-day interval refers to when mice were analyzed after induced deletion, not a duration of thymocyte activity. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [147] Montecino-Rodriguez, 2018, Differential expression of PU.1 and Key T lineage transcription factors distinguishes fetal and adult T Cell development source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In postnatal mice, the entry point is thought to be formed by specialized endothelial cells at the cortical/medullary border of the thymus.

    “In postnatal mice, the entry point is thought to be formed by specialized endothelial cells at the cortical/medullary border of the thymus (129).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [129] Buono, 2016, A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Following an unknown triggering signal, after a variable delay, cells in each cohort migrate centrifugally toward the outer thymic cortex, and cell surface marker expression patterns imply that lineage commitment occurs midway in this migration.

    “Following an unknown triggering signal, after a variable delay (125), the cells in each cohort then begin to migrate centrifugally toward the outer thymic cortex, and cell surface marker expression patterns imply that it is somewhere midway in the course of this migration that the individual cells undergo lineage commitment [reviewed by (60, 130)].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [60] Petrie, 2007, Zoned out: functional mapping of stromal signaling microenvironments in the thymus source
    • cites [130] Love, 2011, Signal integration and crosstalk during thymocyte migration and emigration source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    This difference is now understood to be intrinsically programmed and due to an altered pathway of differentiation in the first-wave cells, which results in T-cell lineage commitment even before entry into the thymus.

    “This is now understood to be intrinsically programmed (136) and due to an altered pathway of differentiation in the first-wave cells, which results in T-cell lineage commitment even before entry into the thymus (137–139).”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [136] Yuan, 2012, Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis source
    • cites [137] Harman, 2005, T/B lineage choice occurs prior to intrathymic Notch signalling source
    • cites [138] Masuda, 2005, Prethymic T-cell development defined by the expression of paired immunoglobulin-like receptors source

      The Results report that commitment to the T/NK/DC lineage occurs in extrathymic organs, and the Discussion describes prethymic progenitors as genetically distinct from intrathymic ones. But the Discussion says these progenitors *may* represent the first phase of thymic immigration; it does not establish an altered differentiation pathway specific to first-wave cells or exclusive commitment to the T-cell lineage. The separate claim of intrinsic programming is attached to citation 136, not this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [139] Berthault, 2017, Asynchronous lineage priming determines commitment to T cell and B cell lineages in fetal liver source

  • May combine two claims.

    Premisecitation

    ETPs derived from first-wave precursors naturally express lower levels of PU.1 than adult ETPs, but are almost unchanged in their ability to generate early fetal T cells when PU.1 is reduced still further (~5 fold) by deletion of the major upstream regulatory element of PU.1.

    “ETPs derived from these precursors naturally express lower levels of PU.1 than adult ETPs, but they are almost unchanged in their ability to generate early fetal T cells when the level of PU.1 is reduced still further (~5 fold) by deletion of the major upstream regulatory element of PU.1 (147).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [147] Montecino-Rodriguez, 2018, Differential expression of PU.1 and Key T lineage transcription factors distinguishes fetal and adult T Cell development source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The earliest fetal thymocytes are different from later waves of developing thymocytes in their abilities to generate particular classes of TCRγδ cells and in their extremely fast differentiation kinetics, both in vivo and in fetal thymic organ culture or stromal coculture systems.

    “It has long been recognized that the earliest fetal thymocytes are different from later waves of developing thymocytes in terms of their abilities to generate particular classes of TCRγδ cells (134) and in terms of their extremely fast differentiation kinetics, both in vivo and in fetal thymic organ culture or stromal coculture systems (104, 133, 135).”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [134] Ikuta, 1990, A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells source
    • cites [104] Scripture-Adams, 2014, GATA-3 dose-dependent checkpoints in early T cell commitment source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [133] Ramond, 2014, Two waves of distinct hematopoietic progenitor cells colonize the fetal thymus source
    • cites [135] Kawamoto, 1997, Hemopoietic progenitors in the murine fetal liver capable of rapidly generating T cells source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These stages span multiple cell cycles in vivo and in vitro.

    “These stages span multiple cell cycles in vivo and in vitro (33, 39, 67, 124).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [33] Yui, 2010, Fine-scale staging of T cell lineage commitment in adult mouse thymus source

      The Results section, “DN2b cells are distinct from DN3 cells” (page unavailable), reports that cultured DN2b cells retained CD25 after 5–8 cell divisions, supporting the in vitro portion. Our copy does not establish that these stages span multiple cell cycles in vivo. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [39] Masuda, 2007, T cell lineage determination precedes the initiation of TCRβ rearrangement source
    • cites [67] Manesso, 2013, Computational modelling of T-cell formation kinetics: output regulated by initial proliferation-linked deferral of developmental competence source

  • May combine two claims.

    Premisecitation

    TCF-1 is essential to maintain adult T-cell production but dispensable in fetal and early postnatal T cell development.

    “For example, the crucial T-lineage transcription factor TCF-1, which plays roles in numerous phases of thymocyte development (95, 140–145), is essential to maintain adult T-cell production but dispensable in fetal and early postnatal T cell development (146).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [146] Schilham, 1998, Critical involvement of Tcf-1 in expansion of thymocytes source

      The Discussion reports a lack of adult T-cell production without Tcf-1, supporting the adult portion of the claim. But the ‘Rapid involution of the adult thymus with age’ section reports fewer fetal thymocytes and changes in thymocyte populations by day 10 after birth; the fetal-progenitor experiments also show a developmental defect. The paper therefore does not support calling Tcf-1 dispensable in fetal and early postnatal development. Page numbers were not available in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The same five-fold diminished level of PU.1 sharply degrades the ability of later fetal hematopoietic stem and progenitor cells to generate T cells at all, in vivo or in vitro, with functional and phenotypic defects evident in mutants in both multipotent progenitors and newly-entered intrathymic ETPs, as early as in the late fetus.

    “In contrast, the same five-fold diminished level of PU.1 sharply degrades the ability of later fetal hematopoietic stem and progenitor cells to generate T cells at all, in vivo or in vitro, with functional and phenotypic defects evident in the mutants in both multipotent progenitors and newly-entered intrathymic ETPs, as early as in the late fetus.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [147] Montecino-Rodriguez, 2018, Differential expression of PU.1 and Key T lineage transcription factors distinguishes fetal and adult T Cell development source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    For many first-wave fetal thymocytes, PU.1 activity may last only a day or two, and is mostly or entirely dispensable.

    “In contrast, for many first-wave fetal thymocytes it may last only a day or two, and is mostly or entirely dispensable (71, 147).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [71] Spain, 1999, T cell development in PU.1-deficient mice source
    • cites [147] Montecino-Rodriguez, 2018, Differential expression of PU.1 and Key T lineage transcription factors distinguishes fetal and adult T Cell development source

      The Discussion (page unavailable) says the early fetal T-cell developmental wave is largely PU.1 independent, supporting the claim’s qualified dispensability point. The study used mice with reduced, not absent, PU.1 expression, and our copy does not establish that PU.1 activity lasts only a day or two in first-wave fetal thymocytes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Pro-T cells that have PU.1 acutely deleted at an early stage differentiate faster along the T lineage and tend to shift to a natural killer-like program more readily than controls.

    “Indeed, pro-T cells that have PU.1 acutely deleted at an early stage do not only differentiate faster along the T lineage; they also tend to shift to a natural killer-like program more readily than controls (79).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [79] Champhekar, 2015, Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU source

      The Results section reports that deleting PU.1 at the ETP or DN2a stage made early T cells differentiate faster than controls. It also reports greater NK-cell production under permissive conditions, but that result concerns progeny of PU.1-deficient fetal liver precursors, not the same early-stage pro-T cells. The claim conflates those populations and omits the NK-development condition. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Findingreasoning

    The highest confidence list of potential PU.1 target genes in pro-T cells is defined as genes that responded reciprocally to gain and loss of PU.1 function within the same DN2a-DN2b developmental interval, and these genes are listed in Table 1.

    “The highest confidence list of potential PU.1 target genes in pro-T cells could be defined as genes that responded reciprocally to gain and loss of PU.1 function within the same DN2a-DN2b developmental interval, and these genes are listed in Table 1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes responding to addition of exogenous PU.1 usually had exogenous PU.1 binding to distal (intronic or neighboring intergenic) sites, whereas genes that had PU.1 binding only to their promoter regions usually did not change expression at all.

    “Genes responding to the addition of exogenous PU.1 usually had the exogenous PU.1 binding to distal (intronic or neighboring intergenic) sites, whereas genes that had PU.1 binding only to their promoter regions usually did not change expression at all.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    These cells also begin to express multiple transcription factors of the Egr and IRF families, and in primary cells, they also upregulate C/EBP family factors.

    “They also begin to express multiple transcription factors of the Egr and IRF families, and in the case of primary cells, they also upregulate C/EBP family factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Scid.adh.2C2 cells, exogenous PU.1 binding opened chromatin at its non-promoter sites within 2 h, increasing H3K27Ac marks a few hours later, and linked genes were predominantly upregulated within 8-24 h.

    “In the “blank slate” background of the Scid.adh.2C2 cell line, exogenous PU.1 binding opened chromatin at its non-promoter sites within 2 h, increasing the “activating” H3K27Ac marks at these sites a few hours later, and the linked genes were predominantly upregulated within 8–24 h.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Most responses of genes linked directly to PU.1 binding sites were positive; direct repression targets were much rarer.

    “In the aggregate, most of the responses of genes linked directly to PU.1 binding sites were positive; direct repression targets were much rarer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PU.1 positively regulates genes encoding specific cytokine receptors (e.g., Pdgfrb), multiple protein tyrosine kinases (Btk, Syk, Hck, Lyn), G-protein coupled receptors (Ffar2, P2ry13, P2ry14), and G protein signaling mediators (Gng2, Rgs18), while repressing other G protein signaling mediators (Gimap and Gbp family members).

    “Potentially important clues to PU.1 roles are the prominence among positively regulated PU.1 targets of genes encoding specific cytokine receptors not yet studied in T-cell biology (e.g., Pdgfrb); multiple protein tyrosine kinases (Btk, Syk, Hck, Lyn); and G-protein coupled receptors (Ffar2, P2ry13, P2ry14) and G protein signaling mediators (Gng2 and Rgs18); while PU.1 represses other G protein s”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Hes1, Tcf12 (HEB), Ets1, and Lef1 are strongly affected in cells making a lineage switch, but none are measurably repressed in cells within the T-cell path.

    “Hes1, Tcf12 (HEB), Ets1, and Lef1 are strongly affected in cells making a lineage switch, but none of these are measurably repressed in cells within the T-cell path.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PU.1 directly promotes expression of cell surface molecules (CD33, CD34, CD44) used as markers for stages in early T-cell development, and drives expression of adhesion molecules (integrins and Siglecs) and cytoskeletal components such as Coro2a and Myo1f.

    “In addition, PU.1 directly promotes expression of cell surface molecules (CD33, CD34, CD44) used as markers for stages in early T-cell development, but which in vivo work to mediate environmental interactions, and it drives expression of adhesion molecules (integrins and Siglecs) as well as cytoskeletal components such as Coro2a and Myo1f.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    PU.1 is a lineage-specifying transcription factor that positively regulates many genes in macrophage, granulocyte, dendritic-cell and B-cell lineages.

    “It is a lineage-specifying transcription factor that positively regulates many genes in the macrophage, granulocyte, dendritic-cell and B-cell lineages.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    B, NK, and T cell development are all affected by defects in PU.1 activity, despite partial complementation by SpiB.

    “Thus, B, NK, and T cell development are all affected by defects in PU.1 activity, despite partial complementation by the related factor SpiB”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Downregulation of PU.1 is important to avoid malignancy in human T cells, and aggressive T-ALL results from translocations promoting sustained elevated PU.1.

    “the downregulation of PU.1 is important to avoid malignancy in human T cells: a specifically aggressive class of human T-acute lymphoblastic leukemias results from translocations that promote abnormally sustained and elevated PU.1 expression (38).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Seki, 2017, Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    PU.1 is encoded by Spi1 and is an ETS-family transcription factor with multiple roles in hematopoiesis.

    “PU.1, encoded by the Spi1 gene, is an ETS-family transcription factor with multiple roles in hematopoiesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Endogenous PU.1 slows developmental progression of pro-T cells even as it supports their early proliferation.

    “It slows developmental progression of pro-T cells even as it supports their early proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The effect of PU.1 on proliferation is conditional and dose-dependent.

    “The effect of PU.1 on proliferation is conditional and dose-dependent, however.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    If timepoints are taken too long after PU.1 deletion, controls progress to the point when endogenous PU.1 is downregulated, so truly PU.1-dependent targets are expressed weakly in controls, and comparisons with knockout samples lose statistical power.

    “If timepoints are taken too long after deletion, the controls progress to the point when endogenous PU.1 is downregulated, so that any truly PU.1-dependent targets are expressed weakly in the controls, and comparisons with the knockout samples again lose statistical power.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The effect of PU.1 expression per se may be part of the normal T-cell program, but under high-level expression it combines with additional conditionally induced mechanisms to produce broader developmental effects that may not only be direct responses to PU.1.

    “Thus, the effect of PU.1 expression per se may be part of the normal T-cell program, but under high-level expression conditions it combines with additional, conditionally induced mechanisms to produce a much broader spectrum of developmental effects that may not only be direct responses to PU.1 itself.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Cre-dependent deletion of a loxP-flanked Spi1 allele is asynchronous, and in an early T-cell population with mixed degrees of Spi1 deletion, cells with inadequate PU.1 levels appear at a selective disadvantage even in vitro.

    “Cre-dependent deletion of a loxP-flanked Spi1 allele (Spi1fl.fl) is asynchronous, and in an early T-cell population with mixed degrees of Spi1 deletion, cells with inadequate PU.1 levels appear to be at a selective disadvantage, even in vitro.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    In newly-committed primary pro-T cells forced to express PU.1, cells crossing the developmental boundary downregulate CD25 and often upregulate CD11b.

    “In newly-committed primary pro-T cells forced to express PU.1, the cells crossing this developmental boundary are seen to downregulate the Notch-dependent DN2/DN3 stage marker, CD25 (Il2ra), and often upregulate the myeloid-associated marker CD11b (Mac1; Itgam).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The Table 1 list under-represents some PU.1 targets that are only expressed in ETP stage.

    “While this list under-represents some PU.1 targets that are only expressed in ETP stage”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The strongest evidence for specific physiological PU.1 effects comes from consensus results from two or more perturbation systems.

    “The strongest evidence for specific physiological PU.1 effects therefore comes from the consensus results from two or more of these perturbation systems.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Rigorous definition of the genes that are directly regulated by PU.1 in pro-T cells has made it possible to investigate the range of mechanisms used by the PU.1 protein to exert these transcriptional effects.

    “rigorous definition of the genes that are directly regulated by PU.1 in pro-T cells has made it possible to investigate the range of mechanisms used by the PU.1 protein to exert these transcriptional effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The fast downregulation of Notch response genes by overexpressed PU.1 may be due to the loss of positive Notch signaling input rather than to a gene-specific mechanism.

    “It is possible that the fast downregulation of Notch response genes, including Hes1, Nrarp, Dtx1, Lef1, and Il2ra, by overexpressed PU.1 is due to the loss of positive Notch signaling input rather than to a gene-specific mechanism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The Notch-inhibitory mechanism is not operating in cells that remain within the T-cell pathway, but becomes prominent in cells that PU.1 causes to transdifferentiate, and would be expected to affect all T-cell genes that use Notch signaling as an obligate positive input.

    “This Notch-inhibitory mechanism is not operating in cells that remain within the T-cell pathway, but it becomes prominent in cells that PU.1 causes to transdifferentiate, and would be expected to affect all T-cell genes that use Notch signaling as an obligate positive input, whether or not PU.1 binds them directly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PU.1 regulates a subset of developmental control genes but is not alone in its actions.

    “Data from multiple studies show that PU.1 regulates a subset of developmental control genes but is not alone in its actions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The PU.1-high stages of thymocyte development are relatively obscure in the context of the whole thymus, yet their accurate regulation is crucial for establishment of immune system homeostasis and avoidance of leukemia.

    “The PU.1-high stages of thymocyte development are relatively obscure in the context of the whole thymus, yet their accurate regulation is crucial for establishment of immune system homeostasis and avoidance of leukemia (125, 126).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [125] Goldschneider, 2006, Cyclical mobilization and gated importation of thymocyte progenitors in the adult mouse: evidence for a thymus-bone marrow feedback loop source
    • cites [126] Martins, 2014, Cell competition is a tumour suppressor mechanism in the thymus source

  • May combine two claims.

    Interpretationreasoning

    Within the T-cell pathway, PU.1 has a specific role in promoting maintenance of certain Phase 1 regulatory genes before commitment, but little role in repressing T-cell differentiation regulators directly.

    “Thus, within the T-cell pathway, PU.1 has a specific role in promoting maintenance of certain Phase 1 regulatory genes before commitment, but little role in repressing T-cell differentiation regulators directly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Some T-cell factors (GATA-3, TCF-1, and Hes1) are already upregulated while PU.1 is still highly expressed, whereas others (Bcl11b, Ets1, Lef1) are upregulated only during the period when PU.1 declines.

    “With respect to PU.1-mediated repression, some T-cell factors are already upregulated while PU.1 is still highly expressed (GATA-3, TCF-1, and the Notch target Hes1), but others are upregulated only during the period when PU.1 declines (Bcl11b, Ets1, Lef1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    While dysregulated PU.1 can cause trans-differentiation to myeloid or dendritic-cell fates, endogenous PU.1 normally plays a protracted role within early T-cell development.

    “While dysregulated PU.1 can cause trans-differentiation to myeloid or dendritic-cell fates, endogenous PU.1 normally plays a protracted role within early T-cell development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    PU.1 is a broad regulator of the properties of the cells that first enter the thymus, and it helps to determine their proliferation and rate of progression to commitment after they arrive.

    “PU.1 is a broad regulator of the properties of the cells that first enter the thymus, and it helps to determine their proliferation and rate of progression to commitment after they arrive.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The first-wave precursor cells enter the thymus by a different route than all subsequent waves: they migrate through cervical-region mesenchyme to the thymic anlage before it is vascularized, and enter directly through the future outer cortex.

    “The first-wave precursor cells, also uniquely, enter the thymus by a different route than all subsequent waves. Instead of entering through the blood vessels near the cortical-medullary junction, these early cells migrate through cervical-region mesenchyme to the thymic anlage before it is vascularized.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    PU.1's target genes are occasionally repressed but mostly activated by PU.1 binding, and they confer on the cells distinctive stage-specific transcription factor expression patterns as well as a rich array of stage-specific cell biological features.

    “Its target genes are occasionally repressed but mostly activated by PU.1 binding, and they confer on the cells distinctive stage-specific transcription factor expression patterns as well as a rich array of stage-specific cell biological features that await proper functional analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The extreme rarity of these very immature cells relative to later-stage thymocytes made them almost impossible to study in depth before the development of in vitro culture systems.

    “Because of the extreme rarity of these very immature cells relative to the later-stage thymocytes at any given time, they were almost impossible to study in depth before the development of in vitro culture systems (88), which have continued to be informative to the present.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Schmitt, 2002, Induction of T cell development from hematopoietic progenitor cells by Delta-like-1 in vitro source

  • May combine two claims.

    Interpretationreasoning

    The first-wave fetal program is less dependent on PU.1 and may rely on relatively low PU.1 activity for its very distinctiveness.

    “Thus, not only is the first-wave fetal program less dependent on PU.1, but also it may rely on relatively low PU.1 activity for its very distinctiveness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    PU.1's positive regulatory role is one result of its strong pattern of binding across the genome, its prominent occupancy of open chromatin sites, and evidence that it helps maintain open chromatin states at bound regulatory sites as long as it is expressed.

    “This positive regulatory role is one result of PU.1's strong pattern of binding across the genome, its prominent occupancy of open chromatin sites, and the evidence that it helps to maintain the open chromatin states at bound regulatory sites as long as it is expressed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These results support a role for PU.1 in delaying differentiation in order to allow more extended proliferation before commitment, with the importance of this role ontogenically scaled to the needs of the developing organism.

    “These results therefore support a role for PU.1 in delaying differentiation in order to allow more extended proliferation before commitment, showing how the importance of this role is ontogenically scaled to the needs of the developing organism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Postnatal thymocytes and any in vitro differentiation cultures seeded with cells from bone marrow or fetal liver from E15 onward are likely to come from true stem cell origins.

    “Thus, postnatal thymocytes and any in vitro differentiation cultures seeded with cells from bone marrow or fetal liver from E15 onward are likely to come from true stem cell origins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The tests of PU.1 function in early pro-T cells done so far present the cells with Notch ligands and cytokines, but could be fundamentally lacking in other molecules presented by the normal thymic environment.

    “The tests of PU.1 function in these early pro-T cells that have been done so far present the cells with Notch ligands and cytokines, but could be fundamentally lacking in other molecules presented by the normal thymic environment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The cells used for in vitro differentiation and in vivo analysis in the reviewed work have all been derived from waves of hematopoiesis that begin with definitive hematopoietic stem cells, which first appear in the mouse fetal liver by about day 11.5 of gestation and may be followed by additional stem-cell waves through the end of gestation (day 20).

    “The cells used for in vitro differentiation as well as in vivo analysis in the work reviewed above have all been derived from waves of hematopoiesis that begin with definitive hematopoietic stem cells, which first appear in the mouse fetal liver by about day 11.5 of gestation and may be followed by additional stem-cell waves through the end of gestation (day 20) (131).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Dzierzak, 2008, Of lineage and legacy: the development of mammalian hematopoietic stem cells source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The first wave of T cell development in the fetus is now thought to arise from these non-stem-cell precursors in the yolk sac.

    “The first wave of T cell development in the fetus is now thought to arise from these non-stem-cell precursors in the yolk sac (132, 133).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [132] Yoshimoto, 2012, Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence source
    • cites [133] Ramond, 2014, Two waves of distinct hematopoietic progenitor cells colonize the fetal thymus source

  • May combine two claims.

    Interpretationnone given

    The number of genes that respond quickly to changes in PU.1 activity may only account for a minority of all genomic sites where PU.1 is found engaged; at other sites, its role could be structural or redundant with other factors.

    “The number of genes that respond quickly to changes in PU.1 activity may only account for a minority of all the genomic sites where PU.1 is found engaged; at other sites, its role could be structural or redundant with other factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    First-wave cells are intrinsically programmed to cut short the stages supported by PU.1-dependent transcriptional regulators, and can dispense with many of the cell biological tools that PU.1 may provide to later-wave successors to navigate the adult or late-fetal thymus.

    “Not only are these cells intrinsically programmed to cut short the stages supported by PU.1-dependent transcriptional regulators, but also they can dispense with many of the cell biological tools that PU.1 may provide to later-wave successors to navigate the adult or late-fetal thymus.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The system-wide impact of PU.1 on other factors suggests that in scenarios where PU.1 is absent, the same T-cell transcription factors might initially choose different binding sites.

    “The system-wide impact of PU.1 on other factors suggests that in scenarios where PU.1 is absent, the same T-cell transcription factors might initially choose different binding sites.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Hematopoietic progenitors express PU.1 before they enter the thymus, but the pattern of its occupancy is not well defined at that stage.

    “Hematopoietic progenitors express PU.1 before they enter the thymus, but the pattern of its occupancy is not well defined at that stage, so the onset of PU.1's pioneering activity in precursors that will eventually generate T cells is not easy to study.”
    Quote in the paperSubstantial claim
94 of 94

  • The paper relies on this without support.

    Developmentally potent transcription factors often transform a cell's identity by positively or negatively regulating the expression of other transcription factors.

    “Developmentally potent transcription factors often transform a cell's identity by positively or negatively regulating the expression of other transcription factors.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PU.1 is a non-canonical pioneer transcription factor that functions as a master regulator of myeloid and lymphoid lineage differentiation.

    “PU.1, a non-canonical pioneer transcription factor that functions as a master regulator of myeloid and lymphoid lineage differentiation18–20.”

    From Lymphoid gene expression supports neuroprotective microglia function (2025) · cites this paper as [19]

    The Introduction (PU.1 Expression in Precursors of T Cells) describes PU.1 as a major regulator of myeloid, dendritic, and B-cell identity, and PU.1 Binding Site Characteristics says it meets the criteria for pioneer-factor activity in early pro-T cells. The paper does not characterize it as “non-canonical,” and its discussion of PU.1 Target Genes says PU.1 is one of several important regulators rather than a sole master regulator of myeloid and lymphoid differentiation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PU.1 plays an important role in early T cell development, while in healthy adults, PU.1-directed actions are largely restricted to the myeloid and B cell compartment.

    “PU.1 plays an important role in early T cell development, while in healthy adults, PU.1-directed actions are largely restricted to the myeloid and B cell compartment [11].”

    From Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β Release (2024) · cites this paper as [11]

    The Introduction (§ PU.1 Expression in Precursors of T Cells; page unavailable) supports PU.1’s role in early T-cell development and says most mature T cells lack detectable PU.1. It also identifies PU.1 activity in dendritic cells and in early T-cell precursors in the postnatal thymus, so the proposed restriction of its actions in healthy adults to myeloid and B-cell compartments is not established by this source. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

64 of the 228 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Petrovick, 1998, Multiple functional domains of AML1: PU, 3915

Cited by

Sorted by citations

Related

Authors
Rothenberg, E. V., Hosokawa, H., & Ungerbäck, J.
Affiliations
California Institute of Technology (US)
Corresponding author
Rothenberg, Ellen V.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-02-20
Volume
10
Pages
228-228
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.00228
PMC
PMC6391351
OpenAlex
W2915813447
Cited by
99
References
228
Citations by year
2026: 11 · 2025: 16 · 2024: 15 · 2023: 16 · 2022: 9 · 2021: 16 · 2020: 9 · 2019: 7
FWCI
3.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Public Health Service (R01AI095943, R01HD076915)
  • Manpei Suzuki Diabetes Foundation
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
PU.1, ETS transcription factors, T cell development, pro-T cells, T cell lineage commitment, coregulator recruitment, gene regulatory networks, thymus
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Hematopoiesis, Humans, Proto-Oncogene Proteins, T-Lymphocytes, Transcription, Genetic, Trans-Activators, Hematopoietic Stem Cell Transplantation, Cell Lineage, Gene Regulatory Networks

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-21.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-21.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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