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Cited by 130DNA Repair MechanismsAlzheimer's disease research and treatmentsGenomic variations and chromosomal abnormalities

Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration

Open access
Dileep, Vishnu, Boix, Carles A., Mathys, Hansruedi, Marco, Asaf, Welch, Gwyneth M., Meharena, Hiruy S., Loon, Anjanet, Jeloka, Ritika +4 more·2023·Cell
DOI 10.1016/j.cell.2023.08.038PMC PMC10697236
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Abstract

Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human postmortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

Persistent neuronal DNA double-strand breaks are linked to mosaic gene fusions, genome structural variations, and progressive 3D genome disruption in Alzheimer’s disease and mouse neurodegeneration models. These changes are enriched in excitatory neurons with DNA damage/senescence signatures and align with transcriptional changes in synaptic, neuronal development, and histone genes.

Key findings

  • In human postmortem prefrontal cortex snRNA-seq (47 ROSMAP participants; 6,180 cells, 5,421 after QC), gene fusions were enriched in AD pathology (adj. p=0.046) and late AD/Braak 5–6 (adj. p=0.00031), particularly in excitatory neurons; this was validated in 10x snRNA-seq of over 2 million cells from 380 individuals (adj. p<0.001).
  • In CK-p25 mice, Step 2 neurons were enriched for gene fusions (p=5.8e−16); mate-pair sequencing showed structural variation increases of 22% in γH2AX-high neurons, 241% in Step 2 neurons, and 201% after persistent etoposide-induced DSBs, while acute etoposide did not increase structural variations.
  • DSBs were enriched at highly expressed and long genes and at fusion junctions; 25 of 27 recurrent DSB cluster genes appeared in human excitatory neuron fusion calls, and AD GWAS genes were longer and enriched among fusion genes.
  • Hi-C showed reduced long-range interactions, ~8.5% of the genome shifting A/B compartments, decreased TAD inclusion ratios, and reduced loop intensities in Step 1/Step 2 neurons; loop loss correlated with downregulated synaptic and neuronal development genes, while histone gene clusters gained de novo loops alongside histone upregulation.

Methods

  • Human postmortem prefrontal cortex from ROSMAP: Smart-seq2 snRNA-seq in 47 individuals and 10x snRNA-seq in 2,026,710 cells from 380 individuals; gene fusions called with STAR-Fusion and analyzed by negative binomial regression with cell- and individual-level covariates.
  • Mouse and primary neuron models: CK-p25 dox-off induction with FANS gates for NeuN/γH2AX, etoposide-treated primary cortical neurons (acute vs persistent DSBs), and Tau P301S mice; assays included mate-pair sequencing, BLISS, in situ Hi-C, Oxford Nanopore cDNA sequencing, and immunofluorescence/immunohistochemistry.
  • Hi-C analyzed with HOMER/Juicer for compartments, TADs, and loops; gene ontology with GOrilla; human RAD21 staining analyzed with linear mixed-effects models.

Limitations

  • Stated: gene fusions represent only a subset of genome structural variations; scRNA-seq is sparse and likely underestimates fusions per cell; PCR artifacts and random ligations are difficult to distinguish from true mosaic fusions, with the assumption that AD/control classification and expression enrichments do not modify these artifacts; the study cannot resolve whether 3D genome disruption is caused directly by unresolved DSBs or by structural variations.
  • Evident from the text: human findings are cross-sectional associations, and causal inference relies on mouse and etoposide models; the full extent of DNA damage-dependent structural variations would require single-cell long-read genome sequencing.

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

Integrity signals

Registry

Crossref · 10.1016/j.cell.2023.08.038

Cites

160 of 160 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 120 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In human post-mortem prefrontal cortex snRNA-seq, gene fusions were significantly enriched in cells from individuals with AD pathology (NIA-Reagan 1-2) compared to non-AD individuals (NIA-Reagan 3-4).

    “we found that gene fusions were significantly enriched in cells from individuals with AD pathology as ascertained by the NIA-Reagan score (pathology diagnosis, AD=1–2 and non-AD=3–4) relative to cells from non-AD individuals (adj. p-value=0.046).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.
  • Findingown data

    Excitatory neurons with higher expression of genes associated with neuronal identity and synaptic function were depleted for gene fusions in both datasets.

    “excitatory neurons with higher expression of genes associated with neuronal identity and synaptic function were depleted for gene fusions in both datasets”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.
  • Findingown data

    In a second 10x snRNA-seq cohort of 380 individuals, gene fusion events were significantly increased in cells from AD individuals compared to non-AD individuals as ascertained by NIA-Reagan and Braak stage.

    “we observed significantly increased gene fusion events (adjusted p-value<0.001) in cells from AD individuals compared to non-AD individuals as ascertained by NIA-Reagan and Braak stage (late-AD versus non/early-AD)”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.
  • Findingown data

    ONT long-read sequencing of cDNA from two AD post-mortem samples identified several gene fusions including RDC genes (e.g. CADM2, CTNND2).

    “We identified several gene fusions which also included RDC genes (e.g. CADM2, CTNND2)”
    Quote in the paperSubstantial claim
  • Findingown data

    Fusion genes from Control, Step 1, and Step 2 neurons had significantly higher expression (from bulk RNA-seq) than expressed genes in neurons.

    “We found that fusion genes from Control, Step 1, and Step 2 neurons had significantly higher expression (from bulk RNA-seq) than expressed genes in neurons”
    Quote in the paperSubstantial claim
  • May combine two claims. 43
  • Borderline: one of the tests for a substantial claim is unclear. 1
  • The quote only partly states this claim. 3
  • Classified as probably not a substantial claim. 39

  • May combine two claims.

    Findingcitation

    In large-scale snRNA-seq across 427 AD and control individuals, there was a significant elevation in cohesin complex expression along with a coordinated increase in DNA damage response in excitatory neurons from subjects with high AD pathology.

    “we identified a significant elevation in cohesin complex expression along with a coordinated increase in DNA damage response in excitatory neurons from subjects with high AD pathology in the large-scale snRNA-seq across 427 AD and control individuals”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Across all genes, both higher transcription levels and increased gene length were significantly associated with increased gene fusions.

    “Across all genes, both higher transcription levels and increased gene length were significantly associated with increased gene fusions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes linked to AD by GWAS were significantly longer than expected and were significantly enriched within fusion genes.

    “genes linked to AD by genome-wide association studies (GWAS) were significantly longer than expected (Figure S3F) and were significantly enriched within fusion genes”
    Quote in the paperSubstantial claim

  • Borderline on S4 (based): unclear from the text. May combine two claims. The quote only partly states this claim.

    Findingown data

    Excitatory neurons in late AD individuals were enriched for gene fusions and showed a higher effect size compared to all other cell types.

    “in this study we report an increased burden of mosaic gene fusions in excitatory neurons in individuals with AD pathology by calling fusion events in single-cell RNA-seq in human post-mortem samples in each cell independently”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.

  • May combine two claims.

    Findingown data

    In primary cortical neurons, acute DSBs (2 h etoposide) had similar levels of structural variations compared to DMSO-treated baseline neurons, whereas persistent DSBs (12 h etoposide) had a markedly higher frequency of structural variation (201% increase) similar to Step 2 neurons.

    “neurons with acute DSBs had similar levels of structural variations compared to DMSO-treated baseline neurons, whereas neurons with persistent DSBs had a markedly higher frequency of structural variation (201% increase) similar to that of the increase observed in Step 2 neurons”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In CK-p25 mice, Step 2 neurons were significantly enriched for gene fusion calls (p=5.8e−16), whereas Step 1 neurons showed a modest increase in gene fusions (p>0.05).

    “Step 2 neurons were significantly enriched for gene fusion calls (p-value=5.8e−16) whereas Step 1 neurons showed a modest increase in gene fusions (p-value > 0.05)”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.

  • May combine two claims.

    Findingown data

    DSBs were enriched at gene fusion junctions, with the highest enrichment in Control cells.

    “we observed enrichment of DSBs at the gene fusion junctions with the highest enrichment in Control cells, indicating gene-fusion junctions are frequent DSB locations”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Gene fusion frequency increased as a function of pseudotime along with genes associated with senescence, similar to the Step 2 signature.

    “gene fusion frequency increased as a function of pseudo time, along with genes associated with senescence, similar to the Step 2 signature”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.

  • May combine two claims.

    Findingown data

    In mate-pair sequencing, Step 2 neurons had a much higher frequency of structural variation events (241% increase), whereas Step 1 neurons had structural variation frequency similar to Control neurons.

    “Step 2 neurons had a much higher frequency of structural variation events (241% increase), whereas the structural variation frequency of Step 1 neurons was similar to that of Control neurons”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    snRNA-seq revealed increased gene expression of Lamin B1 (Lmnb1) in Step 1 neurons and a subsequent decrease in expression from Step 1 to Step 2.

    “snRNA-seq revealed increased gene expression of another nuclear architectural protein Lamin B1 (Lmnb1) in Step 1 neurons and a subsequent decrease in expression from Step 1 to Step 2”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    More loops showed a reduction than a gain in intensity, and loop loss was much more pronounced in Step 2 than in Step 1 neurons.

    “Overall, more loops showed a reduction than a gain in intensity, and loop loss was much more pronounced in Step 2 than in Step 1 neurons”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lamin B1 intensity decreased after 6 weeks of induction, consistent with snRNA-seq.

    “Thereafter, Lamin B1 intensity decreased after 6 weeks of induction, consistent with the snRNA-seq”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TAD definitions showed an overall significant decrease in Step 1 that was exacerbated in Step 2.

    “This analysis revealed an overall significant decrease in the TAD definitions in Step 1 that was exacerbated in Step 2”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Reduction in loop intensity was strongly associated with higher percentages of down-regulated genes in both Step 1 and Step 2 neurons and with lower percentages of up-regulated genes.

    “Reduction in loop intensity was strongly associated with higher percentages of down-regulated genes in both Step 1 and Step 2 neurons and with lower percentages of up-regulated genes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The enrichment of DSBs at loop boundaries was lowest in Step 1, followed by Step 2.

    “The enrichment of DSBs at loop boundaries was lowest in Step 1, followed by Step 2”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Tau P301S mice, Hi-C showed a decreased number of chromatin loops and a significant decrease in TAD integrity as measured by inclusion ratio.

    “Hi-C in P301S neurons showed a decreased number of chromatin loops and a significant decrease in TAD integrity as measured by inclusion ratio”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a net decrease in the intensity of long-range interactions above 1 Mb in Step 1 neurons, even more pronounced in Step 2 neurons with intensity decreasing from 0.5 Mb.

    “Overall, there was a net decrease in the intensity of long-range interactions above 1 Mb, in Step 1 neurons. This was even more pronounced in Step 2 neurons with the intensity of long-range interactions decreasing from 0.5 Mb”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Immunohistochemistry of Lamin B1 in CK-p25 mice induced for 2 weeks revealed increased Lamin B1 and abnormalities in the structure of Lamin B1 in neurons bearing DSBs.

    “Immunohistochemistry of Lamin B1 in CK-p25 mice induced for 2 weeks revealed increased Lamin B1 and abnormalities in the structure of Lamin B1 in neurons bearing DSBs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Approximately 8.5% of the genome shifted compartments and these changes were generally progressive from Step 1 to Step 2.

    “approximately 8.5% of the genome shifted compartments and these changes were generally progressive from Step 1 to Step 2”
    Quote in the paperSubstantial claim

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

    Findingcitation

    Another upregulated histone gene, H2AFV, codes for H2A.Z, whose increase is associated with persistent DNA damage, brain aging, and is negatively associated with memory formation.

    “Another upregulated histone gene, H2AFV, codes for H2A.Z, whose increase is associated with persistent DNA damage, brain aging, and is negatively associated with memory formation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Several histones were upregulated in human AD in excitatory neurons along with upregulation of the cohesin complex genes.

    “we found that several histones were upregulated in human AD in excitatory neurons along with the upregulation of the cohesin complex genes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two hours of etoposide treatment was sufficient to induce DSBs, as measured by γH2AX staining, but not sufficient to accumulate structural variation.

    “The 2 hours of treatment with Etoposide was sufficient to induce DSBs, as measured by yH2AX staining (Figure S2G), but not sufficient to accumulate structural variation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There is a general loss of TAD definition and loop intensities especially in Step 2 senescence-like neurons along with differential regulation of several genes associated with neuronal identity.

    “We observed a general loss of TAD definition and loop intensities especially in Step 2 senescence-like neurons along with differential regulation of several genes associated with neuronal identity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Changes in the 3D genome aligned with transcriptional changes overall, with reduced loop intensities having a striking correlation with the down-regulation of genes.

    “Changes in the 3D genome aligned with transcriptional changes overall, with reduced loop intensities having a striking correlation with the down-regulation of genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DNA double-strand breaks lead to mosaic genome structural variations and the disruption of 3D genome organization in neurons.

    “Overall, our work demonstrates that DNA double-strand breaks lead to mosaic genome structural variations and the disruption of 3D genome organization in neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Persistent DSBs and delayed repair in Step 1 neurons may increase the chance of repair errors and cause them to transition into Step 2 neurons with increased genome structural variations.

    “These results suggest that the persistent DSBs and delayed repair in Step 1 neurons may increase the chance of repair errors and cause them to transition into Step 2 neurons with increased genome structural variations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Loops with increased intensity did not have a consistent relationship with differential gene expression, suggesting that the association between loop gain and gene expression is context-dependent.

    “loops with increased intensity did not have a consistent relationship with differential gene expression, suggesting that the association between loop gain and gene expression is context-dependent”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.

    “Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.”
    • Also stated in: § Introduction · boosted
      “Our results demonstrate the disruption of genome stability and the 3D genome organization mediated by DSBs as pathological steps in the progression of neurodegenerative diseases.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.

  • May combine two claims.

    Interpretationown data

    The study shows increased gene fusions, genome structural variations, and changes in 3D genome organization in neurons harboring DSBs.

    “We show increased gene fusions, genome structural variations, and changes in 3D genome organization in neurons harboring DSBs.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.

  • May combine two claims.

    Premisecitation

    NHEJ is error-prone and can cause genome structural variations, potentially leading to gene fusions with pathological gain or loss of function.

    “NEHJ is error-prone and can cause genome structural variations, potentially leading to gene fusions with pathological gain or loss of function”
    Quote in the paperSubstantial claim0 of 3 sources checked
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  • Classified as probably not a substantial claim.

    Premisecitation

    Structural variations have the potential to rewire genes with ectopic regulatory elements.

    “structural variations have the potential to rewire genes with ectopic regulatory elements”
    Quote in the paperSubstantial claim0 of 3 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chromatin accessibility has been shown to be disrupted in the AD brain.

    “Chromatin accessibility has also been shown to be disrupted in the AD brain”
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    Premisecitation

    The 3D genome is actively regulated during learning and memory formation.

    “There is now emerging evidence that the 3D genome is actively regulated during learning and memory formation”
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    The cohesin complex is an important architectural protein that organizes the 3D genome and is also important in DSB repair.

    “The cohesin complex is an important architectural protein that organizes the 3D genome and is also important in DSB repair”
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    Premisecitation

    Disruption of 3D genome organization has been demonstrated in neurodevelopmental and neurodegenerative disorders such as Huntington's disease, Fragile X syndrome, and Down syndrome.

    “the disruption of 3D genome organization has been demonstrated in neurodevelopmental and neurological neurodegenerative disorders such as Huntington’s disease, Fragile X syndrome, Down syndrome, etc.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Meharena HS, Marco A, Dileep V, Lockshin ER, Akatsu GY, Mullahoo J, Watson LA, Ko T, Guerin LN, Abdurrob F, (2022). Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell 29, 116– 130.e7. 10.1016/J.STEM.2021.12.002. 34995493 PMC8805993 source

      Not checked in the free run.

    • cites [43] Sun JH, Zhou L, Emerson DJ, Phyo SA, Titus KR, Gong W, Gilgenast TG, Beagan JA, Davidson BL, Tassone F, (2018). Disease-Associated Short Tandem Repeats Colocalize with Chromatin Domain Boundaries. Cell. 10.1016/j.cell.2018.08.005. PMC6175607 30173918 source

      Not checked in the free run.

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

    Premisecitation

    The accompanying manuscript by Xiong et al. describes widespread changes in cell-type specific chromatin accessibility within excitatory neurons in human AD samples, termed epigenome erosion.

    “the accompanying manuscript by Xiong et al. describes widespread changes in cell-type specific chromatin accessibility within excitatory neurons in human AD samples which they term “epigenome erosion””
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Xiong X, James BT, Boix CA, Park Y, Galani K, Victor MB, Sun N, Hou L, Dileep V, Ho L-L, (2023). Single-cell epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion. Cell 186. PMC10782612 37774680 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Chromatin loops enable interactions between enhancers and promoters enabling fine control of gene expression, in addition to regulation mediated by transcription factors and other epigenetic modifications.

    “Chromatin loops enable interactions between enhancers and promoters enabling fine control of gene expression, in addition to the regulation mediated by transcription factors and other epigenetic modifications”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Schoenfelder S, and Fraser P (2019). Long-range enhancer–promoter contacts in gene expression control. Nat. Rev. Genet. 10.1038/s41576-019-0128-0. 31086298 source

      Not checked in the free run.

    • cites [98] Kim JH, Rege M, Valeri J, Dunagin MC, Metzger A, Titus KR, Gilgenast TG, Gong W, Beagan JA, Raj A, (2019). LADL: light-activated dynamic looping for endogenous gene expression control. Nat. Methods. 10.1038/s41592-019-0436-5. PMC6599567 31235883 source

      Not checked in the free run.

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

    Premisecitation

    Lamin B1 controls release of DSB repair protein 53BP1 and overexpression of Lamin B1 impedes DSB repair leading to persistent DSBs.

    “Lamin B1 has been shown to control the release of DSB repair protein 53BP1 and overexpression of LaminB1 impeded DSB repair leading to persistent DSBs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Etourneaud L, Moussa A, Rass E, Genet D, Willaume S, Chabance-Okumura C, Wanschoor P, Picotto J, Thézé B, Dépagne J, (2021). Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage. Sci. Adv. 7, 3799– 3826. 10.1126/SCIADV.ABB3799. PMC8397269 34452908 source

      Not checked in the free run.

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

    Premisecitation

    Loop extrusion mediated by cohesin and CTCF mediates the formation of chromatin loops and self-interacting TADs.

    “loop extrusion mediated by cohesin and CTCF mediates the formation of chromatin loops and self-interacting Topologically Associating Domains (TADs)”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [77] Rao SSP, Huang SC, Glenn St Hilaire B, Engreitz JM, Perez EM, Kieffer-Kwon KR, Sanborn AL, Johnstone SE, Bascom GD, Bochkov ID, (2017). Cohesin Loss Eliminates All Loop Domains. Cell. 10.1016/j.cell.2017.09.026. PMC5846482 28985562 source

      Not checked in the free run.

    • cites [81] Hansen AS, Cattoglio C, Darzacq X, and Tjian R (2018). Recent evidence that TADs and chromatin loops are dynamic structures. Nucleus 9, 20. 10.1080/19491034.2017.1389365. 29077530 PMC5990973 source

      Not checked in the free run.

    • cites [82] Davidson IF, Bauer B, Goetz D, Tang W, Wutz G, and Peters JM (2019). DNA loop extrusion by human cohesin. Science (80-.). 366, 1338– 1345. 10.1126/science.aaz3418. 31753851 source

      Not checked in the free run.

    • cites [83] Kim Y, Shi Z, Zhang H, Finkelstein IJ, and Yu H (2019). Human cohesin compacts DNA by loop extrusion. Science 366, 1345– 1349. 10.1126/SCIENCE.AAZ4475. 31780627 PMC7387118 source

      Not checked in the free run.

    • cites [84] Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, and Ren B (2012). Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions. Nature 485, 376. 10.1038/NATURE11082. 22495300 PMC3356448 source

      Not checked in the free run.

    • cites [85] Nora EP, Lajoie BR, Schulz EG, Giorgetti L, Okamoto I, Servant N, Piolot T, Van Berkum NL, Meisig J, Sedat J, (2012). Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nat. 2012 4857398 485, 381– 385. 10.1038/nature11049. PMC3555144 22495304 source

      Not checked in the free run.

    • cites [86] Nora EP, Goloborodko A, Valton AL, Gibcus JH, Uebersohn A, Abdennur N, Dekker J, Mirny LA, and Bruneau BG (2017). Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Cell. 10.1016/j.cell.2017.05.004. PMC5538188 28525758 source

      Not checked in the free run.

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

    Premisecitation

    Loop boundaries are hotspots for TOP2B-mediated DNA breaks in T-cells and B-cells.

    “loop boundaries are hotspots for TOP2 B-mediated DNA breaks in T-cells and B-cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Canela A, Maman Y, Jung S, Wong N, Callen E, Day A, Kieffer-Kwon K-R, Pekowska A, Zhang H, Rao SSP, (2017). Genome Organization Drives Chromosome Fragility. Cell 170, 507– 521.e18. 10.1016/j.cell.2017.06.034. 28735753 PMC6133249 source

      Not checked in the free run.

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

    Premisecitation

    Lamin B1 plays a crucial role in 3D genome organization by tethering heterochromatin to the nuclear periphery.

    “Lamin B1 plays a crucial role in the 3D genome organization by tethering heterochromatin to the nuclear periphery”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Solovei I, Wang AS, Thanisch K, Schmidt CS, Krebs S, Zwerger M, Cohen TV, Devys D, Foisner R, Peichl L, (2013). LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152, 584– 598. 10.1016/j.cell.2013.01.009. 23374351 source

      Not checked in the free run.

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

    Premisecitation

    The A compartment is largely localized to the nuclear interior, while the B compartment is tethered to the nuclear periphery by Lamin B1.

    “While the A compartment is largely localized to the nuclear interior, the B compartment is tethered to the nuclear periphery by Lamin B1”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Lieberman-Aiden E, Van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, (2009). Comprehensive mapping of long range interactions reveals folding principles of the human genome. Science 326, 289. 10.1126/SCIENCE.1181369. 19815776 PMC2858594 source

      Not checked in the free run.

    • cites [92] van Steensel B, and Belmont AS (2017). Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin, and Gene Repression (NIH Public Access) 10.1016/j.cell.2017.04.022. PMC5532494 28525751 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increased stochastic DSB burden strains DNA repair resources, leading to defective DNA repair and genome structural variations that disproportionately affect hotspots of DNA breaks such as highly expressed genes, long genes, and loop anchors.

    “We propose that the increased stochastic DSB burden strains the DNA repair resources, leading to defective DNA repair and genome structural variations that disproportionately affect hotspots of DNA breaks such as highly expressed genes, long genes, and loop anchors.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A neo-TAD caused by structural variation was associated with higher expression of the oncogene MYC in neuroblastomas.

    “For instance, a neo-TAD caused by structural variation was associated with higher expression of the oncogene MYC in neuroblastomas23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Dixon JR, Xu J, Dileep V, Zhan Y, Song F, Le VT, Yardımcı GG, Chakraborty A, Bann DV, Wang Y, (2018). Integrative detection and analysis of structural variation in cancer genomes. Nat. Genet. 10.1038/s41588-018-0195-8. PMC6301019 30202056 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genomic mosaicism by retrotransposition of LINE-1 elements has been associated with the neuronal genome and the derepression of LINE-1 elements has been associated with senescence.

    “Indeed, genomic mosaicism by retro transposition of LINE-1 elements has been associated with the neuronal genome and the derepression of LINE-1 elements has been associated with senescence129–131.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [129] Bedrosian TA, Quayle C, Novaresi N, and Gage FH (2018). Early life experience drives structural variation of neural genomes in mice. Science (80-.). 10.1126/science.aah3378. 29567711 source

      Not checked in the free run.

    • cites [130] De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD, (2019). LINE-1 derepression in senescent cells triggers interferon and inflammaging. Nature 566, 73. 10.1038/S41586-018-0784-9. 30728521 PMC6519963 source

      Not checked in the free run.

    • cites [131] Valle F. Della, Reddy P, Yamamoto M, Liu P, Saera-Vila A, Bensaddek D, Zhang H, Martinez JP, Abassi L, Celii M, (2022). LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes. Sci. Transl. Med. 14. 10.1126/scitranslmed.abl6057. 35947677 source

      Not checked in the free run.

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

    Premisecitation

    Genome structural variations can lead to gene fusions and are often drivers of cancer.

    “genome structural variations can lead to gene fusions and are often drivers of cancer”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Edwards PAW (2010). Fusion genes and chromosome translocations in the common epithelial cancers. J. Pathol. 220, 244– 254. 10.1002/PATH.2632. 19921709 source

      Not checked in the free run.

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

    Premisecitation

    Erosion of epigenetic information, TAD insulation, and cell identity was recently reported in a mouse model with inducible DNA damage (ICE mouse model) accompanied by brain aging and cognitive decline.

    “Interestingly, erosion of epigenetic information, TAD insulation, and cell identity was recently reported in a mouse model with inducible DNA damage (ICE mouse model) accompanied by brain aging and cognitive decline132.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Yang JH, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, Salfati EL, Blanchette M, Munding EM, Bhakta M, (2023). Loss of epigenetic information as a cause of mammalian aging. Cell 186. 10.1016/j.cell.2022.12.027. PMC10166133 36638792 source

      Not checked in the free run.

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

    Premisecitation

    X-ray radiation-induced DSBs increased the segregation of TAD fibroblasts.

    “Surprisingly, X-ray radiation-induced DSBs increased the segregation of TAD fibroblasts54.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Sanders JT, Freeman TF, Xu Y, Golloshi R, Stallard MA, Hill AM, San Martin R, Balajee AS, and McCord RP (2020). Radiation-induced DNA damage and repair effects on 3D genome organization. Nat. Commun. 2020 111 11, 1– 14. 10.1038/s41467-020-20047-w. PMC7710719 33268790 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Step 1 showed lower DSB enrichments for highly transcribed and long genes, and DSBs were supported by fewer UMIs, suggesting that Step 1 DSBs are largely stochastic.

    “Surprisingly, Step 1 showed lower DSB enrichments for highly transcribed and long genes, and DSBs were supported by fewer UMIs, suggesting that Step 1 DSBs are largely stochastic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Genomic mosaicism is an important driver of senescence in neurons and could contribute to the pathogenesis of neurodegenerative disease.

    “These observations combined with our results suggest that genomic mosaicism is an important driver of senescence in neurons and could contribute to the pathogenesis of neurodegenerative disease.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A recent study identified an increase in mosaicism due to recombination between Alu and L1 elements in Parkinson's and Alzheimer's disease.

    “Recently, a study identified an increase in mosaicism due to recombination between Alu and L1 elements in Parkinson’s and Alzheimer’s disease120.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Pascarella G, Hon CC, Hashimoto K, Busch A, Luginbühl J, Parr C, Hin Yip W, Abe K, Kratz A, Bonetti A, (2022). Recombination of repeat elements generates somatic complexity in human genomes. Cell 185, 3025– 3040.e6. 10.1016/J.CELL.2022.06.032. 35882231 source

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

    Premisecitation

    Previous studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions) in neurodegeneration.

    “Previous studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions in neurodegeneration)124–128.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [124] Lodato MA, Rodin RE, Bohrson CL, Coulter ME, Barton AR, Kwon M, Sherman MA, Vitzthum CM, Luquette LJ, Yandava CN, (2018). Aging and neurodegeneration are associated with increased mutations in single human neurons. Science (80-.). 359, 555– 559. 10.1126/science.aao4426. PMC5831169 29217584 source

      Not checked in the free run.

    • cites [125] Miller MB, Yue Huang A, Kim J, Zhou Z, Kirkham SL, Maury EA, Ziegenfuss JS, Reed HC, Neil JE, Rento L, (2022). Somatic genomic changes in single Alzheimer’s disease neurons. | Nat. | 604. 10.1038/s41586-022-04640-1. PMC9357465 35444284 source

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    • cites [126] Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, Liu CS, Park C, Kennedy G, Long T, (2018). Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature. 10.1038/s41586-018-0718-6. PMC6391999 30464338 source

      Not checked in the free run.

    • cites [127] Kousi M, Boix C, Park YP, Mathys H, Sledzieski S, Peng Z, Bennett DA, Tsai L-H, and Kellis M (2022). Single-cell mosaicism analysis reveals cell-type-specific somatic mutational burden in Alzheimer’s Dementia. bioRxiv, 2022.04.21.489103. 10.1101/2022.04.21.489103. source

      Not checked in the free run.

    • cites [128] McConnell MJ, Moran JV, Abyzov A, Akbarian S, Bae T, Cortes-Ciriano I, Erwin JA, Fasching L, Flasch DA, Freed D, (2017). Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science (80-.). 356. 10.1126/science.aal1641. PMC5558435 28450582 source

      Not checked in the free run.

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

    Premisecitation

    Genome structural variations have been shown to cause pathological TAD fusions and create neo-TADs in several cancers.

    “Interestingly, genome structural variations have been shown to cause pathological TAD fusions and create neo-TADs in several cancers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Dixon JR, Xu J, Dileep V, Zhan Y, Song F, Le VT, Yardımcı GG, Chakraborty A, Bann DV, Wang Y, (2018). Integrative detection and analysis of structural variation in cancer genomes. Nat. Genet. 10.1038/s41588-018-0195-8. PMC6301019 30202056 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent study proposed that DSBs can act as roadblocks to loop extrusion.

    “A recent study proposed that DSBs can act as roadblocks to loop extrusion32.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Arnould C, Rocher V, Finoux AL, Clouaire T, Li K, Zhou F, Caron P, Mangeot PE, Ricci EP, Mourad R, (2021). Loop extrusion as a mechanism for formation of DNA damage repair foci. Nature 590, 660– 665. 33597753 PMC7116834 source

      Not checked in the free run.

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

    Premisecitation

    Accumulation of DNA damage can lead to a senescence-like state in neurons and has been implicated in the progression of AD.

    “accumulation of DNA damage can lead to a senescence-like state in neurons and has been implicated in the progression of AD”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [121] Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, Gonos ES, Thrasivoulou C, Jill Saffrey M, Cameron K, (2012). Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996. 10.1111/J.1474-9726.2012.00870.X. 22882466 PMC3533793 source

      Not checked in the free run.

    • cites [122] Saez-Atienzar S, and Masliah E (2020). Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat. Rev. Neurosci. 2020 218 21, 433– 444. 10.1038/s41583-020-0325-z. PMC12548380 32601397 source

      Not checked in the free run.

    • cites [123] Welch G, and Tsai L (2022). Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease. EMBO Rep. 23. 10.15252/EMBR.202154217. PMC9171412 35499251 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DSBs are repaired via the classical non-homologous end joining (NHEJ) pathway in post-mitotic cells and can lead to genome structural variations.

    “DSBs are repaired via the classical non-homologous end joining (NHEJ) pathway in post-mitotic cells and can lead to genome structural variations”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Richardson C, and Jasin M (2000). Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697– 700. 10.1038/35015097. 10864328 source

      Not checked in the free run.

    • cites [19] Ferguson DO, and Alt FW (2001). DNA double strand break repair and chromosomal translocation: Lessons from animal models. Oncogene 20, 5572– 5579. 10.1038/sj.onc.1204767. 11607810 source

      Not checked in the free run.

    • cites [20] Lin C, Yang L, Tanasa B, Hutt K, Ju B. gun, Ohgi K, Zhang J, Rose DW, Fu XD, Glass CK, (2009). Nuclear Receptor-Induced Chromosomal Proximity and DNA Breaks Underlie Specific Translocations in Cancer. Cell 139, 1069– 1083. 10.1016/j.cell.2009.11.030. 19962179 PMC2812435 source

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

    Study design and conductreasoning

    In the current study, the authors are unable to resolve the precise role of each of these components.

    “In the current study, we are unable to resolve the precise role of each of these components.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Bio-replicate 1 of Step 2 neurons was excluded from differential A/B compartment statistical significance owing to its lower read depth.

    “Bio-replicate 1 of Step 2 neurons was excluded from the analysis of differential A/B compartment statistical significance owing to its lower read depth.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The disruption in the 3D genome organization could be caused both directly by unresolved DSBs and by genome structural variations.

    “The disruption in the 3D genome organization could be caused both directly by unresolved DSBs and by genome structural variations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Studies have shown senescence-associated 3D genome reorganization in dividing cell types.

    “Additionally, studies have shown senescence-associated 3D genome reorganization in dividing cell types42,140–143.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [42] Meharena HS, Marco A, Dileep V, Lockshin ER, Akatsu GY, Mullahoo J, Watson LA, Ko T, Guerin LN, Abdurrob F, (2022). Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell 29, 116– 130.e7. 10.1016/J.STEM.2021.12.002. 34995493 PMC8805993 source

      Not checked in the free run.

    • cites [140] Chandra T, Ewels PA, Schoenfelder S, Furlan-Magaril M, Wingett SW, Kirschner K, Thuret JY, Andrews S, Fraser P, and Reik W (2015). Global reorganization of the nuclear landscape in senescent cells. Cell Rep. 10, 471– 483. 10.1016/J.CELREP.2014.12.055. 25640177 PMC4542308 source

      Not checked in the free run.

    • cites [141] Criscione SW, Cecco M. De, Siranosian B, Zhang Y, Kreiling JA, Sedivy JM, and Neretti N (2016). Reorganization of chromosome architecture in replicative cellular senescence. Sci. Adv. 2. 10.1126/SCIADV.1500882. PMC4788486 26989773 source

      Not checked in the free run.

    • cites [142] Iwasaki O, Tanizawa H, Kim KD, Kossenkov A, Nacarelli T, Tashiro S, Majumdar S, Showe LC, Zhang R, and Noma K ichi (2019). Involvement of condensin in cellular senescence through gene regulation and compartmental reorganization. Nat. Commun. 2019 101 10, 1– 20. 10.1038/s41467-019-13604-5. PMC6908677 31831736 source

      Not checked in the free run.

    • cites [143] Zirkel A, Nikolic M, Sofiadis K, Mallm JP, Brackley CA, Gothe H, Drechsel O, Becker C, Altmüller J, Josipovic N, (2018). HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types. Mol. Cell 70, 730– 744.e6. 10.1016/j.molcel.2018.03.030. 29706538 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims. The quote only partly states this claim.

    Study design and conductown data

    Gene fusion enrichment was quantified using a negative binomial generalized linear model with cell-level and individual-level covariates, and p-values adjusted using Benjamini-Hochberg.

    “We quantified the enrichment of putative fusion events at the cell level across conditions using a negative binomial generalized linear model where we model the number of fusions in each cell with an offset term for the number of reads captured for that cell (log(n_counts)).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Previous studies have shown the importance of histones in DNA damage response, senescence, brain aging, neuronal identity, and memory formation.

    “Previous studies have shown the importance of histones in DNA damage response, senescence, brain aging, neuronal identity, and memory formation100–102,136–139.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [100] Kalocsay M, Hiller NJ, and Jentsch S (2009). Chromosome-wide Rad51 Spreading and SUMO-H2A.Z-Dependent Chromosome Fixation in Response to a Persistent DNA Double-Strand Break. Mol. Cell 33, 335– 343. 10.1016/J.MOLCEL.2009.01.016. 19217407 source

      Not checked in the free run.

    • cites [101] Stefanelli G, Azam AB, Walters BJ, Brimble MA, Gettens CP, Bouchard-Cannon P, Cheng HYM, Davidoff AM, Narkaj K, Day JJ, (2018). Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus. Cell Rep. 22, 1124– 1131. 10.1016/J.CELREP.2018.01.020. 29386101 PMC5820781 source

      Not checked in the free run.

    • cites [102] Zovkic IB, Paulukaitis BS, Day JJ, Etikala DM, and Sweatt JD (2014). Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nat. 2014 5157528 515, 582– 586. 10.1038/nature13707. PMC4768489 25219850 source

      Not checked in the free run.

    • cites [136] Isermann A, Mann C, and Rübe CE (2020). Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence. Int. J. Mol. Sci. 21, 1– 20. 10.3390/IJMS21239130. PMC7729917 33266246 source

      Not checked in the free run.

    • cites [137] Contrepois K, Coudereau C, Benayoun BA, Schuler N, Roux PF, Bischof O, Courbeyrette R, Carvalho C, Thuret JY, Ma Z, (2017). Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nat. Commun. 2017 81 8, 1– 18. 10.1038/ncomms14995. PMC5436145 28489069 source

      Not checked in the free run.

    • cites [138] Rübe CE, Bäumert C, Schuler N, Isermann A, Schmal Z, Glanemann M, Mann C, and Scherthan H (2021). Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis. npj Aging Mech. Dis. 2021 71 7, 1– 11. 10.1038/s41514-021-00060-z. PMC8016850 33795696 source

      Not checked in the free run.

    • cites [139] Funk OH, Qalieh Y, Doyle DZ, Lam MM, and Kwan KY (2022). Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity. Proc. Natl. Acad. Sci. U. S. A. 119. 10.1073/pnas.2116956119. PMC9371731 35930666 source

      Not checked in the free run.

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

    Study design and conductown data

    In situ Hi-C was performed with three replicates, each a pool of 3 CK-p25 mice forebrains.

    “Three replicates were performed, where each replicate was a pool of 3 CK-p25 mice forebrains (Table S1, page 16).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All animal experiments were approved by the Committee for Animal Care of the Division of Comparative Medicine at MIT.

    “All the experiments were approved by the Committee for Animal Care of the Division of Comparative Medicine at the Massachusetts Institute of Technology (MIT) and carried out at MIT.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    At least two coronal slices were used for each mouse for image quantification.

    “At least two coronal slices were used for each mouse for image quantification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Chimeric molecules arising through PCR artifacts and random ligations during library preparation are difficult to distinguish from chimeric molecules arising from true mosaic gene fusions.

    “While relatively uncommon, chimeric molecules arising through PCR artifacts and random ligations during library preparation are difficult to distinguish from chimeric molecules arising from true mosaic gene fusions.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    For the 10x dataset, the 'SM_171013Tsa' batch was removed due to markedly lower quality, number of reads, and number of genes detected per cell.

    “We removed the ‘SM_171013Tsa’ batch from the original dataset due to markedly lower quality, number of reads, and number of genes detected per cell.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductown data

    Human RAD21 staining differences between control and AD were assessed with a linear mixed-effects model with individual as random effect and likelihood ratio test.

    “We fitted a linear mixed-effects model with the percentage of high RAD21 neurons or mean intensity of RAD21 as the response variable, group (Control or AD) as the fixed effect, and individual (ID) as the random effect.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductreasoning

    Single-cell RNA seq provides a sparse readout of gene expression and is likely to generally underestimate the number of gene fusions in each cell.

    “Single-cell RNA seq provides a sparse readout of gene expression and is likely to generally underestimate the number of gene fusions in each cell.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    For single-nucleus Smart-seq2, a subset of 47 individuals comprised of 24 and 23 age and sex-matched cases with AD pathology and no pathologic AD was selected.

    “For single-nucleus Smart-seq2, we selected a subset of 47 individuals comprised of 24 and 23 age and sex-matched cases with AD pathology (NIA-Reagan 1–2) and no pathologic AD (NIA-Reagan 3–4).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Human subjects were selected from ROSMAP, with informed consent and IRB approval.

    “Informed consent was obtained from each subject, and the Religious Orders Study and Rush Memory and Aging Project were each approved by an Institutional Review Board (IRB) of Rush University Medical Center.”
    Quote in the paperSubstantial claim
73 of 73

  • The authors state this as an assumption.

    Gene fusions detected from snRNA-seq reads are a valid proxy for genome structural variations in neurons.

    “using STAR-fusion to detect chimeric snRNA-seq reads mapping between two genes as a proxy for genome structural variations”
    “increased levels of gene fusions as a proxy for increased genome structural variation”

  • The authors state this as an assumption.

    AD vs. Control classification and various gene expression pattern enrichments explored in this do not modify PCR artifacts and random ligations during library preparation.

    “We make the assumption that AD vs. Control classification and various gene expression pattern enrichments explored in this do not modify PCR artifacts and random ligations during library preparation.”

  • The paper relies on this without support.

    Genome structural variations can bring ectopic regulatory elements next to genes causing pathological up or down-regulation of genes.

    “Genome structural variations can bring ectopic regulatory elements next to genes causing pathological up or down-regulation of genes.”

  • The paper relies on this without support.

    Gene fusions at important neural genes can result in a pathological gain or loss of their function and result in defects in neuronal function.

    “Gene fusions at important neural genes can result in a pathological gain or loss of their function and result in defects in neuronal function.”

  • The paper relies on this without support.

    Gene fusions arise from a subset of genome structural variations.

    “Gene fusions arise from a subset of genome structural variations”
5 of 5

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?

  • Features of premature senescence associated with DSBs and p16 expression have been described in post-mitotic cells such as neurons.

    “However, features of premature senescence associated particularly with DNA double-strand breaks (DSBs) and p16 expression also have been described in post-mitotic cells such as neurons[16, 18, 29].”

    From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [18]

    The Results section on DSB-bearing neurons reports that neurons with increased DSB burden progress to a senescence-like state; the Discussion likewise describes a DSB-mediated senescence-like state in neurons. Our copy does not report p16 expression in those neurons. Its mention of p25 is not evidence for p16 expression. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Recent single-cell studies of human AD revealed links between DNA damage and epigenome erosion during disease progression.

    “Recent single-cell studies of human AD revealed the links between DNA damage and epigenome erosion during disease progression77,78.”

    From Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability (2025) · cites this paper as [77]

    The Discussion links DNA damage to disrupted 3D genome organization, and the Results report single-nucleus findings in human AD samples. But the paper’s Results attribute the specifically named “epigenome erosion” in human AD to an accompanying study; this paper’s direct evidence for progressive DSB-associated 3D genome disruption comes from a mouse model. It therefore supports a related link, but not the full claim as a finding of its human single-cell study. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • These works estimated damage burden by measuring chimeric gene fusions arising from DSBs.

    “These work estimated damage burden by measuring chimeric gene fusions arose from DSBs.”

    From Single-cell parallel analysis of DNA damage and transcriptome reveals selective genome vulnerability (2025) · cites this paper as [77]

    The Results section reports counting chimeric reads to identify gene fusions and comparing fusion burden across cells; it also finds DSBs enriched at fusion junctions. But the Discussion calls fusions a proxy for genome structural variations, not a measure of overall DNA damage burden, and the Limitations section says they capture only a subset of those variations. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The 832 DEGs identified in LOAD spheroid RNA-seq overlap with the recently published gene list from snRNA-seq of postmortem human prefrontal cortex from individuals with AD, with an overlap of 233 signature protein-coding genes of neurodegeneration upregulated in excitatory neurons.

    “we compared 832 DEGs identified in our LOAD spheroid RNA-seq dataset with the recently published gene list from single-nucleus RNA-seq (snRNA-seq) of postmortem human prefrontal cortex from individuals with AD (79). The signature protein-coding genes of neurodegeneration, upregulated in the excitatory neurons in the snRNA-seq, exhibited an overlap of 233 genes (Table S7, page 1).”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [79]

  • Disruption of genome stability and 3D genome organization are pathological steps in progression of AD.

    “a recent study demonstrated that disruption of genome stability and 3D genome organization are pathological steps in progression of AD (79).”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [79]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting mate-pair DNA fragment sizes

    Minor

    The Results say the circularized mate-pair DNA was sheared into 200-300 bp fragments, while the Methods specify an average size of 500 bp for the same step.

1 of 1

Cites

Flagged first, then by citations

2 of the 162 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Dileep, V., Boix, C. A., Mathys, H., Marco, A., Welch, G. M., Meharena, H. S., Loon, A., Jeloka, R., Peng, Z., Bennett, D. A., Kellis, M., & Tsai, L.-H.
Affiliations
  • Massachusetts Institute of Technology (US)
  • MIT Computer Science and Artificial Intelligence Laboratory (US)
  • Rush University Medical Center (US)
  • Broad Institute (US)
Corresponding author
  • Dileep, Vishnu
  • Kellis, Manolis
  • Tsai, Li-Huei
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2023-09
Volume
186
Issue
20
Pages
4404-4421.e20
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2023.08.038
PMC
PMC10697236
OpenAlex
W4387142572
Semantic Scholar
db858b708e9752459a4cefe64a28e29701a12bc8
Cited by
130
References
162
Citations by year
2026: 28 · 2025: 53 · 2024: 41 · 2023: 7 · 2022: 1
FWCI
11.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (P30AG72975, K99 AG073466, R01AG15819, R01AG17917, P30AG10161, R01 AG058002, U01AG46152, U01 NS110453, U01AG61356, NS051874, AG054012, NS102730)
  • Cure Alzheimer&apos;s Fund
  • Alzheimer&apos;s Association (AARF-19-618751)
  • JPB Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (R01AG17917, R01AG15819, P30AG72975, P30AG10161, P2BSP3_151885, U01AG61356, U01AG46152)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
DNA double-strand breaks, neurodegeneration, Alzheimer's disease, structural variants, 3D genome organization, cohesin, DNA repair, cellular senescence, excitatory neurons, genome stability, histone genes
MeSH terms
Alzheimer Disease, Animals, DNA, DNA Repair, Humans, Neurons, Sequence Analysis, RNA, Neurodegenerative Diseases, Genomic Instability, Mice, DNA Breaks, Double-Stranded, Single-Cell Analysis

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 2026-10-10.

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

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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