Gcn5 Is Required for PU.1-Dependent IL-9 Induction in Th9 Cells
Open accessAbstract
Naive CD4+ T cells differentiate into various effector Th subsets depending on the Ags and cytokine microenvironment they encounter. IL-9–secreting Th9 cells are the most recent Th subset to be described. PU.1, one of the transcription factors required for the development of Th9 cells, binds to the Il9 gene. In this study, we show that PU.1 increases histone acetylation at the Il9 locus through direct interactions with histone acetyltransferases. In the absence of PU.1, there is decreased association of Gcn5 and p300/CBP associated factor and increased association of histone deacetylases at the Il9 locus in Th9 cells. Inhibition of histone deacetylase activity augments PU.1-dependent IL-9 production. PU.1 forms a complex with Gcn5, and inhibition of the expression of Gcn5 results in reduced IL-9 production. Moreover, the effects of Gcn5 on IL-9 production are specific as the production of IL-10 and IL-21, two additional cytokines produced by Th9 cells, is not altered after decreased Gcn5 expression. Together, these data define a PU.1-dependent mechanism for altered histone acetylation and expression of the Il9 locus in Th9 cells.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
6 of 6 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Findingown data
TSA treatment does not cause Il10 or Il21 expression in Th9 cells.
“However, TSA does not induce the expression of Il10 and Il21, cytokines produced by Th9 cells (5, 26)(Fig. 1D).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [5] Chang, 2010, The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation, Nat. Immunol. source
The citation follows the description of Il10 and Il21 as cytokines produced by Th9 cells; the TSA-treatment result is attributed to the citing paper’s Fig. 1D. In Results, “Distinct populations secrete IL-10 and IL-9” (page unavailable), the cited paper reports IL-10 production by Th9 cultures, but our copy does not establish Il21 production by those cells (searched: Il21, IL-21). (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [26] Kaplan, 2011, STAT3-dependent IL-21 production from T helper cells regulates hematopoietic progenitor cell homeostasis, Blood source
The Results and discussion section reports that Th9 cells produce IL-21, supporting one part of the cytokine description attached to this citation. Our copy does not establish that Th9 cells produce IL-10. The TSA-treatment result is attributed to the citing paper’s Figure 1D, not established by this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
p300 binding at the Il9 promoter is higher in PU.1-deficient Th9 cells.
“In contrast to previous reports showing that PU.1 recruited p300 to the Igκ locus in B cells (23), there was increased binding of p300 at the Il9 promoter in PU.1-deficient Th9 cells (Fig. 3A).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Bai, 2005, Protein acetylation regulates both PU.1 transactivation and Ig kappa 3′ enhancer activity, J. Immunol. source
- Findingown data
Lowering Gcn5 expression reduces IL-9 production in Th9 cells.
“inhibiting the expression of Gcn5 results in reduced IL-9 production.”
- Also stated in: § Gcn5 is required for IL-9 expression · plain
“Concomitantly, IL-9 production was reduced significantly when Gcn5 expression was inhibited (Fig. 6C).”
Quote in the paperSubstantial claim - Also stated in: § Gcn5 is required for IL-9 expression · plain
- Findingown data
Lowering Gcn5 expression leaves IL-10 and IL-21 production in Th9 cells unchanged.
“the effects of Gcn5 on IL-9 production are specific as the production of IL-10 and IL-21, two additional cytokines produced by Th9 cells, is not altered following decreased Gcn5 expression.”
- Also stated in: § Gcn5 is required for IL-9 expression · plain
“Gcn5 inhibition does not decrease IL-10 and IL-21 production (Fig. 6C).”
Quote in the paperSubstantial claim - Also stated in: § Gcn5 is required for IL-9 expression · plain
- Findingown data
TSA treatment raises H3K14 and H4K5 acetylation at the Il9 locus in wild-type Th9 cells.
“Acetylation of H3K14 and H4K5 was increased after wild-type Th9 cells were treated with TSA (Fig. 1H).”
Quote in the paperSubstantial claim
- Findingown data
When PU.1 is absent from Th9 cells, HDAC binding at the Il9 locus rises.
“In the absence of PU.1, there is decreased association of Gcn5 and PCAF, and increased association of HDACs at the Il9 locus in Th9 cells.”
- Also stated in: § Histone deacetylase inhibitor enhances IL-9 production · plain
“There was significantly enhanced HDAC1 and HDAC2 binding at Il9 promoter (CNS1) in the absence of PU.1 (Fig. 1B).”
Quote in the paperSubstantial claim - Also stated in: § Histone deacetylase inhibitor enhances IL-9 production · plain
- Findingown data
When PU.1 is absent from Th9 cells, Gcn5 and PCAF bind less to the Il9 locus.
“In the absence of PU.1, there is decreased association of Gcn5 and PCAF, and increased association of HDACs at the Il9 locus in Th9 cells.”
- Also stated in: § Altered histone acetylase binding at the Il9 locus · plain
“We observed decreased recruitment of both Gcn5 and PCAF at Il9 CNS1 and CNS0 in the absence of PU.1 (Fig. 3A).”
Quote in the paperSubstantial claim - Also stated in: § Altered histone acetylase binding at the Il9 locus · plain
- Findingown data
In Th9 cells, PU.1 bound to DNA associates directly with Gcn5.
“PU.1 forms a complex with Gcn5”
- Also stated in: § PU.1 associates with Gcn5 · plain
“DNA-bound PU.1 was able to precipitate Gcn5 from wild-type lysates in the presence of WT oligonucleotide (Fig. 5A).”
Quote in the paperSubstantial claim - Also stated in: § PU.1 associates with Gcn5 · plain
- Findingown data
Th9 cells lacking PU.1 release much less IL-9 than wild-type Th9 cells.
“PU.1-deficient Th9 cells secreted significantly lower amounts of IL-9 than wild-type Th9 cells (Fig. 1G).”
Quote in the paperSubstantial claim - Findingown data
TSA treatment increases PU.1 and IRF4 binding at the Il9 promoter.
“There was increased PU.1 and IRF4 binding to Il9 promoter after TSA treatment (Fig. 1I)”
Quote in the paperSubstantial claim - Findingown data
Total H3 and H4 levels at the Il9 promoter are similar in wild-type and PU.1-deficient Th9 cells.
“As a control we compared total H3 and H4 at Il9 promoter between WT and PU.1-deficient Th9 cells and observed no difference in total histone content at the locus (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
The PU.1 DNA-binding mutant does not induce IL-9 in PU.1-deficient Th9 cultures.
“The DNA binding mutant did not induce IL-9 when transduced into PU.1-deficient Th9 cultures (data not shown).”
Quote in the paperSubstantial claim - Findingown data
The PU.1 activation domain mutant does not restore Gcn5 binding at the Il9 promoter in PU.1-deficient Th9 cells.
“However, cells transduced with the activation domain mutant failed to rescue Gcn5 binding (Fig. 5C), further confirming the importance of the activation domain.”
Quote in the paperSubstantial claim - Findingown data
Gcn5 binding at the Il9 promoter is much lower in PU.1-deficient Th9 cells given control retrovirus than in wild-type cells.
“PU.1-deficient Th9 cells transduced with control retrovirus had significantly attenuated Gcn5 binding at the Il9 promoter compared to wild-type cells (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
DNA-bound PU.1 needs its activation domain to pull down Gcn5 efficiently.
“DNA-bound PU.1 requires the activation domain to efficiently precipitate Gcn5 (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data
The PU.1 activation domain mutant is much less able to restore IL-9 in PU.1-deficient Th9 cells.
“In contrast, the activation domain mutant had a significantly diminished ability to rescue IL-9 in PU.1-deficient Th9 cells.”
Quote in the paperSubstantial claim - Findingown data
Acetylation of H3K9/18, H4K5, H4K8, and H4K16 is markedly lower at Il9 CNS1 and CNS0 in PU.1-deficient Th9 cells.
“Acetylation of H3K9/18, H4K5, H4K8, and H4K16 was decreased significantly at the Il9 CNS1 and CNS0.”
Quote in the paperSubstantial claim - Findingown data
H3K14 acetylation at the Il9 promoter is markedly lower in PU.1-deficient Th9 cells.
“We observed significantly attenuated histone acetylation of histone H3K14 at the Il9 promoter in PU.1-deficient Th9 cells (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
Lowering Gcn5 expression does not change PU.1 or IRF4 binding at the Il9 promoter.
“Decreased Gcn5 expression did not alter PU.1 or IRF4 binding to the Il9 promoter (Fig. 6D).”
Quote in the paperSubstantial claim - Findingown data
H3K9/18, H4K5, and H4K8 acetylation at the Il9 promoter is lower when Gcn5 is inhibited.
“We observed acetylation of H3K9/18, H4K5 and H4K8 at the Il9 promoter was attenuated when Gcn5 was inhibited (Fig. 6E).”
Quote in the paperSubstantial claim - Findingown data
H3K27 and H3K36 acetylation at the Il9 locus is similar in wild-type and PU.1-deficient Th9 cells.
“However, there was no difference in acetylation of H3K27 and H3K36 between wild-type and PU.1-deficient Th9 cells (Fig. 4A).”
Quote in the paperNot a substantial claim - Findingown data
DNA-bound PU.1 does not pull down PCAF from wild-type or PU.1-deficient Th9 lysates.
“PCAF was not precipitated from either wild-type or PU.1-deficient Th9 lysates (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Full-length PU.1 restores Gcn5 binding at the Il9 promoter in PU.1-deficient Th9 cells.
“Full-length PU.1 was able to rescue Gcn5 binding in PU.1-deficient Th9 cells (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
DNA-bound PU.1 pulls down Gcn5 from wild-type Th9 lysates when a consensus PU.1-binding oligonucleotide is present.
“DNA-bound PU.1 was able to precipitate Gcn5 from wild-type lysates in the presence of WT oligonucleotide (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
DNA-bound PU.1 does not pull down Gcn5 from PU.1-deficient Th9 extracts.
“However, Gcn5 was not precipitated when consensus oligonucleotide was used with PU.1-deficient Th9 extracts (Fig. 5A).”
Quote in the paperSubstantial claim - Interpretationown data
The results outline a PU.1-dependent pathway for changed histone acetylation and Il9 expression in Th9 cells.
“Together, these data define a PU.1-dependent mechanism for altered histone acetylation and expression of the Il9 locus in Th9 cells.”
Quote in the paperSubstantial claim - Interpretationown data
In Th9 cells, PU.1 boosts histone acetylation at the Il9 locus by directly contacting histone acetyltransferases.
“In this study we show that PU.1 increases histone acetylation at the Il9 locus through direct interactions with histone acetyltransferases (HAT).”
Quote in the paperSubstantial claim - Interpretationown data
The activation domain of PU.1 is essential for IL-9 induction.
“Together, these data suggest that the activation domain of PU.1 is critical for the induction of IL-9.”
Quote in the paperSubstantial claim - Interpretationreasoning
Lower Gcn5 and PCAF binding at the Il9 locus contributes to reduced Il9 transcription when PU.1 is absent.
“The expression of Gcn5 and PCAF do not change upon the loss of PU.1 (Fig. 3B), suggesting that the decreased association of Gcn5 and PCAF with the Il9 locus contributes to reduced Il9 transcription.”
Quote in the paperSubstantial claim - Interpretationown data
PU.1 controls acetylation of specific histone residues at the Il9 locus.
“Overall, these data indicate that PU.1 regulates specific histone acetylation at the Il9 locus.”
Quote in the paperSubstantial claim - Interpretationown data
The data offer a mechanism for PU.1-dependent Il9 regulation in developing Th9 cells.
“Together, our data provide a mechanism for PU.1-dependent Il9 regulation in developing Th9 cells.”
Quote in the paperSubstantial claim - Interpretationown data
PU.1 is needed for specific HATs to associate with the Il9 promoter.
“Thus, PU.1 is required for the association of specific HATs to the Il9 promoter.”
Quote in the paperSubstantial claim - Interpretationown data
The acidic transactivation domain of PU.1 is also needed for IL-9 induction.
“In this report, we document that the acidic transactivation domain was also required for IL-9 induction.”
Quote in the paperSubstantial claim - Interpretationown data
PU.1 is not essential for p300 binding at the Il9 locus in Th9 cells.
“We observed increased p300 association at the Il9 locus in the absence of PU.1, suggesting that PU.1 is not critical for p300 binding to Il9, and that other transcription factors may mediate p300 recruitment in Th9 cells.”
Quote in the paperSubstantial claim - Interpretationreasoning
PU.1 uses several domains to control the Th9 phenotype.
“Thus, PU.1 uses multiple domains to regulate the Th9 phenotype.”
Quote in the paperSubstantial claim
- May combine two claims. 16
May combine two claims.
FindingcitationPU.1-deficient Th9 cells given control retrovirus show fewer IL-9-secreting cells, less IL-9 production, and more IL-4 production than wild-type Th9 cells.
“PU.1-deficient Th9 cells transduced with control retrovirus had significantly reduced IL-9-secreting cells and IL-9 production compared to wild-type Th9 cells, and increased production of IL-4, as previously described (Chang et al, 2009) (Fig. 2C–E).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Chang et al, 2009 source
The Results section on T-cell signaling and Th2 cytokine production reports higher cytokine secretion from PU.1-deficient Th2 cultures than from wild-type cultures, which offers limited support for the IL-4 comparison. The cited paper does not report the claimed Th9 control-retrovirus comparison or measurements of IL-9-secreting cells and IL-9 production; its retroviral-transduction methods describe Th1 and Th2 cells instead. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationGcn5-dependent histone acetylation probably increases binding of T cell receptor-induced factors such as NF-κB or NFAT that matter for Il9 expression after antigen receptor stimulation, or may help general transcription factors including RNA polymerase II.
“Gcn5-dependent histone acetylation likely increases binding of T cell receptor-induced factors such as NF-κB or NFAT that are important for Il9 gene expression following antigen receptor stimulation (27) or may facilitate the function of general transcription factors including RNA polymerase II (49).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [27] Jash, 2012, Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-κB (NF-κB)-mediated interleukin-9 (IL-9) transactivation, J. Biol. Chem. 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 - cites [49] Sansó, 2011, Gcn5 facilitates Pol II progression, rather than recruitment to nucleosome-depleted stress promoters, in Schizosaccharomyces pombe, Nucleic Acids Res. source
May combine two claims.
Findingown dataFull-length PU.1 raises both the proportion and the intensity of IL-9-secreting T cells.
“Full length PU.1 enhances both the percentage and the intensity of IL-9-secreting T cells (Fig. 2A and B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBlocking HDAC activity raises IL-9 output in wild-type Th9 cells, but not in cells lacking PU.1.
“Inhibiting histone deacetylase activity augments PU.1-dependent IL-9 production.”
- Also stated in: § Histone deacetylase inhibitor enhances IL-9 production · plain
“Although TSA was able to significantly increase IL-9 production from wild-type Th9 cells, addition of TSA in PU.1-deficient Th9 cultures did not increase IL-9 production (Fig. 1G).”
Quote in the paperSubstantial claim- Also stated in: § Histone deacetylase inhibitor enhances IL-9 production · plain
May combine two claims.
Findingown dataPU.1 variants missing the transactivation domain or carrying a DNA-binding point mutation do not induce IL-9.
“In contrast, cells transduced with either the transactivation mutant or with the DNA-binding mutant retroviruses failed to induce IL-9 (Fig. 2A and B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTSA treatment raises Sfpi1 expression but leaves Irf4 expression unchanged in Th9 cells.
“We observed an increase in Sfpi1 expression, but no change in Irf4 expression in Th9 cells (Fig. 1E).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataGcn5-specific siRNA markedly lowers Gcn5 mRNA and Gcn5 binding at the Il9 promoter in Th9 cells.
“Th9 cells transfected with Gcn5-specific siRNA had significantly decreased Gcn5 mRNA, and decreased Gcn5 binding to the Il9 promoter (Fig. 6A, B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLosing PU.1 does not change Gcn5, PCAF, or p300 expression.
“Loss of PU.1 did not alter the expression of these HATs (Fig. 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFull-length PU.1 brings IL-9 production in PU.1-deficient Th9 cells back to wild-type levels and suppresses IL-4 production.
“However, full-length PU.1 was able to recover IL-9 production in PU.1-deficient Th9 cells to a level similar to wild-type Th9 cells transduced with control retrovirus, and repress production of IL-4 (Fig. 2C–E).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBoth the activation domain and the DNA-binding domain of PU.1 are needed for IL-9 induction.
“Overall, these data suggest that the activation domain and DNA-binding domain of PU.1 are required for the induction of IL-9.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataHDAC inhibition raises IL-9 production, and this tracks with greater histone acetylation and greater PU.1 and IRF4 binding at the Il9 promoter.
“Overall, these data demonstrate that HDAC inhibition leads to increased IL-9 production, and this correlates with increased histone acetylation and increased PU.1 and IRF4 binding to the Il9 promoter.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDNA-bound PU.1 associates directly with Gcn5, but not with PCAF.
“These results suggest that DNA-bound PU.1 is able associate directly with Gcn5, but not PCAF.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataGcn5 inhibition lowers IL-9 production and reduces acetylation of Gcn5-targeted lysine residues at the Il9 promoter.
“Together, these data suggest that Gcn5 inhibition leads to reduced IL-9 production concomitant with decreased histone acetylation of Gcn5-targeted lysine residues at the Il9 promoter.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataPU.1 associates with Gcn5, and its activation domain is essential for Gcn5 binding at the Il9 promoter.
“Together, these data demonstrate that PU.1 associates with Gcn5 and that the activation domain is critical for Gcn5 binding to Il9 promoter.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataLower Gcn5 expression leaves IL-10 and IL-21 production unchanged, showing that the Il9 locus is a specific Gcn5 target in Th9 cells.
“However, diminished Gcn5 expression did not change IL-10 and IL-21 production demonstrating that, in Th9 cells, the Il9 locus is a specific target of Gcn5.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe authors propose a mechanism from their data: PU.1 binds the Il9 promoter in developing Th9 cells, leading to complex formation and recruitment of Gcn5-containing chromatin remodeling complexes, plus indirect PCAF recruitment, which raises histone acetylation.
“Based on our data, we propose the following mechanism. PU.1 binds to the Il9 promoter in developing Th9 cells. This results in complex formation and recruitment of Gcn5-containing chromatin remodeling complexes, as well as an indirect recruitment of PCAF, leading to increased histone acetylation.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Before this study, the mechanism by which PU.1 drives Il9 expression in Th9 cells was unknown.
“However, a mechanism for PU.1-dependent Il9 expression in Th9 cells has not been defined.”
The paper relies on this without support.
TSA selectively blocks class I and II HDACs.
“Wild-type Th9 cells were treated with TSA an antifungal antibiotic that selectively inhibits class I and II HDACs.”
Cites
Chromatin modifications and their function
Kouzarides, T. (2007) · Cell · doi:10.1016/j.cell.2007.02.005 · Cited by 10,883 · see citing works
The language of covalent histone modifications
Strahl, B. D., & Allis, C. D. (2000) · Nature · doi:10.1038/47412 · Cited by 8,679 · cited 1× · see citing works
“backbone thereby facilitating the accessibility of trans-acting factors to the gene (13).”
BackgroundDifferentiation of Effector CD4 T Cell Populations
Zhu, J., Yamane, H., & Paul, W. E. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101212 · Cited by 3,452 · cited 1× · see citing works
“bet, GATA3, and RORgt as lineage-specific transcriptional regulators (1).”
BackgroundAmino Acid Sequences Common to Rapidly Degraded Proteins: The PEST Hypothesis
Rogers, S. W., Wells, R., & RECHSTEINER, M. C. (1986) · Science · doi:10.1126/science.2876518 · Cited by 2,565 · cited 1× · see citing works
“(35, 36), although in most reports the PEST domain was not required for transactivation (8, 32, 33, 37, 38).”
BackgroundPEST sequences and regulation by proteolysis
RECHSTEINER, M. C., & Rogers, S. W. (1996) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(96)10031-1 · Cited by 1,645 · cited 1× · see citing works
“(35, 36), although in most reports the PEST domain was not required for transactivation (8, 32, 33, 37, 38).”
BackgroundVeldhoen, M., Uyttenhove, C., van Snick, J., Helmby, H., Westendorf, A., Buer, J., Martin, B., Wilhelm, C., & Stockinger, B. (2008) · Nature Immunology · doi:10.1038/ni.1659 · Cited by 1,213 · see citing works
Acetylation: a regulatory modification to rival phosphorylation?
Kouzarides, T. (2000) · The EMBO Journal · doi:10.1093/emboj/19.6.1176 · Cited by 1,155 · cited 1× · see citing works
“biosynthesis in Saccharomyces cerevisiae before its role in histone acetylation and transcription was appreciated (19).”
BackgroundDardalhon, V., Awasthi, A., Kwon, H., Galileos, G., Gao, W., Sobel, R. A., Mitsdoerffer, M., Strom, T. B., Elyaman, W., Ho, I.-C., et al. (2008) · Nature Immunology · doi:10.1038/ni.1677 · Cited by 1,122 · see citing works
Histone acetyltransferase complexes: one size doesn't fit all
Lee, K. K. W., & Workman, J. L. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2145 · Cited by 1,091 · cited 1× · see citing works
“1, the association of Gcn5 and PCAF—two proteins found in multiprotein chromatin remodeling complexes (20)—with the Il9 locus was decreased or eliminated.”
BackgroundThe macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene
Klemsz, M. J., McKercher, S. R., Celada, A., Van Beveren, C., & Maki, R. A. (1990) · Cell · doi:10.1016/0092-8674(90)90219-5 · Cited by 954 · see citing works
(1996) · Europe PMC (PubMed Central) · Cited by 659 · see citing works
Histone deacetylases, transcriptional control, and cancer
Cress, W. D., & Seto, E. (2000) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(200007)184:1 · Cited by 619 · see citing works
Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines
Kuo, M.-H., Brownell, J. E., Sobel, R. E., Ranalli, T. A., Cook, R. G., Edmondson, D. G., Roth, S. Y., & Allis, C. D. (1996) · Nature · doi:10.1038/383269a0 · Cited by 596 · see citing works
Chang, H.-C., Sehra, S., Goswami, R., Yao, W., Yu, Q., Stritesky, G. L., Jabeen, R., McKinley, C., Ahyi, A.-N., Han, L., et al. (2010) · Nature Immunology · doi:10.1038/ni.1867 · Cited by 577 · cited 9× · see citing works
“1 results in decreased IL-9 production in vitro, as well as in vivo coincident with diminished allergic inflammation (5).”
BackgroundInfluentialSelf-citationInterferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells
Staudt, V., Bothur, E., Klein, M., Lingnau, K., Reuter, S., Grebe, N., Gerlitzki, B., Hoffmann, M., Ulges, A., Taube, C., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.07.014 · Cited by 554 · cited 1× · see citing works
“to activate IFN regulatory factor 4 (IRF4) and potentially other factors as part of a transcription factor network in Th9 cells (6, 7).”
BackgroundHistone deacetylases as regulators of inflammation and immunity
Shakespear, M. R., Halili, M. A., Irvine, K. M., Fairlie, D. P., & Sweet, M. J. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.04.001 · Cited by 546 · cited 1× · see citing works
“HDAC activity has been shown to regulate T cell development and function (45).”
BackgroundTranscriptional activators direct histone acetyltransferase complexes to nucleosomes
Utley, R. T., Ikeda, K., Grant, P. A., Côté, J., Steger, D. J., Eberharter, A., John, S., & Workman, J. L. (1998) · Nature · doi:10.1038/28886 · Cited by 499 · see citing works
The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence.
Karim, F. D., Urness, L. D., Thummel, C. S., Klemsz, M. J., McKercher, S. R., Celada, A., Van Beveren, C., Maki, R. A., Gunther, C. V., & Nye, J. A. (1990) · Genes & Development · doi:10.1101/gad.4.9.1451 · Cited by 499 · see citing works
Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines
Otte, A. P. (1997) · UvA-DARE (University of Amsterdam) · Cited by 480 · see citing works
Zhang, W., Bone, J. R., Edmondson, D. G., Turner, B. M., & Dent, S. (1998) · The EMBO Journal · doi:10.1093/emboj/17.11.3155 · Cited by 322 · see citing works
Hagemeier, C., Bannister, A. J., Cook, A., & Kouzarides, T. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.4.1580 · Cited by 303 · cited 1× · see citing works
“(35, 36), although in most reports the PEST domain was not required for transactivation (8, 32, 33, 37, 38).”
BackgroundPU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis
Dakic, A., Metcalf, D., Di Rago, L., Mifsud, S., Wu, L., & Nutt, S. L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050075 · Cited by 297 · cited 1× · see citing works
“1 gene deletion (Sfpi1) on C57BL/6 background were previously described (24) and were mated to mice expressing Cre transgene under the control of Lck promoter.”
BackgroundLoss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development
Xu, A. W., Edmondson, D. G., Evrard, Y. A., Wakamiya, M., Behringer, R. R., & Dent, S. (2000) · Nature Genetics · doi:10.1038/79973 · Cited by 267 · cited 1× · see citing works
“Gcn5-null embryos die during embryogenesis (28).”
STAT6-dependent regulation of Th9 development
Goswami, R., Jabeen, R., Yagi, R., Pham, D., Zhu, J., Goenka, S., & Kaplan, M. H. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102840 · Cited by 240 · cited 3× · see citing works
“1 is one of the transcription factors required for the development of Th9 cells downstream of the TGF-b signal (5, 6).”
BackgroundSelf-citationMOZ is essential for maintenance of hematopoietic stem cellsPreprint
Katsumoto, T., Aikawa, Y., Iwama, A., Ueda, S., Ichikawa, H., Ochiya, T., & Kitabayashi, I. (2006) · Genes & Development · doi:10.1101/gad.1393106 · Cited by 224 · cited 2× · see citing works
“1 interacts with the HATs p300, Tip60, and MOZ (23, 42, 43).”
BackgroundPU.1 Expression Delineates Heterogeneity in Primary Th2 Cells
Chang, H.-C., Zhang, S., Thieu, V. T., Slee, R. B., Bruns, H. A., Laribee, R. N., Klemsz, M. J., & Kaplan, M. H. (2005) · Immunity · doi:10.1016/j.immuni.2005.03.016 · Cited by 159 · cited 2× · see citing works
“1 has two functions: it limits Th2 responses by interacting with GATA3 but also binds directly to Il9 to facilitate chromatin remodeling and transactivation (5, 11, 12).”
BackgroundSelf-citationStopka, T., Amanatullah, D. F., Papetti, M., & Skoultchi, A. I. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600834 · Cited by 154 · see citing works
Kominato, Y., Galson, D. L., Waterman, W. R., Webb, A. C., & Auron, P. E. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.1.59 · Cited by 146 · cited 1× · see citing works
“(35, 36), although in most reports the PEST domain was not required for transactivation (8, 32, 33, 37, 38).”
BackgroundChromatin Remodeling and Transcriptional Regulation
Luo, R., & Dean, D. C. (1999) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/91.15.1288 · Cited by 146 · cited 3× · see citing works
“HDAC inhibition creates a hyperacetylated state; however, not all gene expression is increased (17, 18).”
BackgroundResultIFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines
Ahyi, A.-N. N., Chang, H.-C., Dent, A. L., Nutt, S. L., & Kaplan, M. H. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803302 · Cited by 137 · see citing works
Self-citationGrausenburger, R., Bilić, I., Boucheron, N., Zupkovitz, G., El-Housseiny, L., Tschismarov, R., Zhang, Y., Rembold, M., Gaisberger, M., Hartl, A. J., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903610 · Cited by 130 · see citing works
Shin, M. K., & Koshland, M. E. (1993) · Genes & Development · doi:10.1101/gad.7.10.2006 · Cited by 126 · see citing works
Li, J., Lin, Q., Wang, W., Wade, P. A., & Wong, J. (2002) · Genes & Development · doi:10.1101/gad.962502 · Cited by 126 · see citing works
The symphony of the ninth: the development and function of Th9 cells
Jabeen, R., & Kaplan, M. H. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.02.001 · Cited by 112 · see citing works
Self-citationNagulapalli, S., Pongubala, J. M., & Atchison, M. L. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.9.4330 · Cited by 110 · see citing works
Activation of Transcription by PU.1 Requires both Acidic and Glutamine Domains
Klemsz, M. J., & Maki, R. A. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.1.390 · Cited by 93 · see citing works
Surprising new roles for PU.1 in the adaptive immune response
Carotta, S., Wu, L., & Nutt, S. L. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00955.x · Cited by 93 · cited 1× · see citing works
“1 function has been described, and although it is considered a pioneer factor in cellular differentiation (21, 22), only limited work has examined the interaction of PU.”
BackgroundMaturation-related histone modifications in the PU.1 promoter regulate Th9-cell development
Ramming, A., Druzd, D., Leipe, J., Schulze‐Koops, H., & Skapenko, A. (2012) · Blood · doi:10.1182/blood-2011-11-392589 · Cited by 85 · see citing works
Regulating Il9 transcription in T helper cells
Perumal, N. B., & Kaplan, M. H. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.01.006 · Cited by 85 · cited 2× · see citing works
“noncoding sequences 5-prime of the Il9 gene (25) (Fig.”
BackgroundSelf-citationPU.1 and Haematopoietic Cell Fate: Dosage Matters
Mak, K. S., Funnell, A. P. W., Pearson, R. C. M., & Crossley, M. (2011) · International Journal of Cell Biology · doi:10.1155/2011/808524 · Cited by 77 · cited 1× · see citing works
“1 function has been described, and although it is considered a pioneer factor in cellular differentiation (21, 22), only limited work has examined the interaction of PU.”
BackgroundJash, A., Sahoo, A., Kim, G.-C., Chae, C.-S., Hwang, J.-S., Kim, J.-E., & Im, S.-H. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.340356 · Cited by 75 · cited 2× · see citing works
“1 or IRF4 binding to Il9, Gcn5-dependent histone acetylation likely increases binding of TCR-induced factors such as NF-kB or NFAT that are important for Il9 gene expression after Ag receptor stimulation (27) or may facilitate the function of general transcription factors including RNA polymerase II (49).”
BackgroundPU.1 regulates TCR expression by modulating GATA-3 activity
Chang, H.-C., Han, L., Jabeen, R., Carotta, S., Nutt, S. L., & Kaplan, M. H. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900363 · Cited by 66 · cited 2× · see citing works
“duced IL-9–secreting cells and IL-9 production compared with those of WT Th9 cells and increased production of IL-4, as previously described (12) (Fig.”
BackgroundSelf-citationLoss of PU.1 Expression Following Inhibition of Histone Deacetylases
Laribee, R. N., & Klemsz, M. J. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.5160 · Cited by 64 · see citing works
Tip60 Is a Cell-Type-Specific Transcriptional Regulator
Hlubek, F., Löhberg, C. R., Meiler, J., et al. (2001) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a002901 · Cited by 58 · cited 2× · see citing works
“1 interacts with the HATs p300, Tip60, and MOZ (23, 42, 43).”
BackgroundSansó, M., Vargas-Pérez, I., Quintales, L., Antequera, F., Ayté, J., & Hidalgo, E. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr255 · Cited by 51 · cited 1× · see citing works
“1 or IRF4 binding to Il9, Gcn5-dependent histone acetylation likely increases binding of TCR-induced factors such as NF-kB or NFAT that are important for Il9 gene expression after Ag receptor stimulation (27) or may facilitate the function of general transcription factors including RNA polymerase II (49).”
BackgroundFisher, R. C., Olson, M. C., Pongubala, J. M. R., Perkel, J. M., Atchison, M. L., Scott, E. W., & Simon, M. C. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.7.4347 · Cited by 49 · cited 1× · see citing works
“The ETS homology DNA binding domain is at the C-terminal end, and the acidic and glutamine-rich domains in the N-terminal end act as transactivation domains (8, 9).”
BackgroundKaplan, M. H., Glosson, N. L., Stritesky, G. L., Yeh, N., Kinzfogl, J., Rohrabaugh, S. L., Goswami, R., Pham, D., Levy, D. E., Brutkiewicz, R. R., et al. (2011) · Blood · doi:10.1182/blood-2011-02-334367 · Cited by 41 · cited 1× · see citing works
“Il10 and Il21, cytokines produced by Th9 cells (5, 26) (Fig.”
BackgroundSelf-citationProtein Acetylation Regulates Both PU.1 Transactivation and Igκ 3′ Enhancer Activity
Bai, Y., Srinivasan, L., Perkins, L., & Atchison, M. L. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.8.5160 · Cited by 38 · see citing works
Functional analysis of PU.1 domains in monocyte‐specific gene regulation
Nishiyama, C., Nishiyama, M., Ito, T., Masaki, S., Masuoka, N., Yamane, H., Kitamura, T., Ogawa, H., & Okumura, K. (2004) · FEBS Letters · doi:10.1016/s0014-5793(04)00116-4 · Cited by 34 · cited 1× · see citing works
“(35, 36), although in most reports the PEST domain was not required for transactivation (8, 32, 33, 37, 38).”
BackgroundContext dependent transactivation domains activate the immunoglobulin mu heavy chain gene enhancer.
Erman, B., & Sen, R. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00843.x · Cited by 31 · cited 1× · see citing works
“(35, 36), although in most reports the PEST domain was not required for transactivation (8, 32, 33, 37, 38).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Gerlach, K., Hwang, Y., Nikolaev, A., Atreya, R., Dornhoff, H., Steiner, S., Lehr, H.-A., Wirtz, S., Vieth, M., Waisman, A., et al. (2014) · Nature Immunology · doi:10.1038/ni.2920 · Cited by 407 · see citing works
The development and in vivo function of T helper 9 cells
Kaplan, M. H., Hufford, M. M., & Olson, M. R. (2015) · Nature Reviews Immunology · doi:10.1038/nri3824 · Cited by 384 · see citing works
Self-citationTh9 cells: differentiation and disease
Kaplan, M. H. (2013) · Immunological Reviews · doi:10.1111/imr.12028 · Cited by 319 · see citing works
Self-citationPolyamine metabolism is a central determinant of helper T cell lineage fidelity
Puleston, D. J., Baixauli, F., Sanin, D. E., Edwards-Hicks, J., Villa, M., Kabat, A. M., Kamiński, M. M., Stanckzak, M., Weiss, H. J., Grzes, K. M., et al. (2021) · Cell · doi:10.1016/j.cell.2021.06.007 · Cited by 295 · see citing works
“To probe if reducing H3k9 acetylation could restore normal TH lineage commitment, we inhibited theHATKAT2A, whichmediates H3k9 acetylation in T cells (Castillo et al., 2019; Gao et al., 2017; Ghosh et al., 2016; Goswami and Kaplan, 2012).”
Effector T Helper Cell Subsets in Inflammatory Bowel Diseases
Imam, T., Park, S., Kaplan, M. H., & Olson, M. R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01212 · Cited by 269 · see citing works
“1 binds to the Il9 promoter and alters histone acetylation (192).”
BackgroundSelf-citationTh9 cell development requires a BATF-regulated transcriptional network
Jabeen, R., Goswami, R., Awe, O., Kulkarni, A., Nguyen, E., Attenasio, A., Walsh, D., Olson, M. R., Kim, M. H., Tepper, R. S., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69489 · Cited by 225 · see citing works
Self-citationTh9 cells, new players in adaptive immunity
Schmitt, E., Klein, M., & Bopp, T. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.10.004 · Cited by 189 · see citing works
Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter
Reese, T. A., Wakeman, B. S., Choi, H. S., Hufford, M. M., Huang, S. C., Zhang, X., Buck, M. D., Jezewski, A. J., Kambal, A., Liu, C., et al. (2014) · Science · doi:10.1126/science.1254517 · Cited by 186 · see citing works
Self-citationTh9 and other IL-9-producing cells in allergic asthma
Koch, S., Sopel, N., & Finotto, S. (2016) · Seminars in Immunopathology · doi:10.1007/s00281-016-0601-1 · Cited by 162 · see citing works
Possible pathogenic role of T helper type 9 cells and interleukin (IL)-9 in atopic dermatitis
Ma, L., Xue, H.-B., Guan, X.-H., Shu, C.-M., Zhang, J. ‐., & Yu, J. (2013) · Clinical & Experimental Immunology · doi:10.1111/cei.12198 · Cited by 115 · see citing works
Transcription factor PU.1 and immune cell differentiation (Review)
Li, G., Hao, W., & Hu, W. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4763 · Cited by 98 · see citing works
“Goswami and Kaplan demonstrated that PU.1 promoted IL‑9 expression by recruiting the Gcn5 histone acetyltransferase to the IL9 locus and promoting the expression of additional genes enriched in Th9 cells (70).”
IL-9 and Th9 cells in health and diseases—From tolerance to immunopathology
Li, J., Chen, S., Xiao, X., Zhao, Y. L., Ding, W., & Li, X. C. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2017.07.004 · Cited by 89 · see citing works
“1 also regulates permissive chromatin remodeling at the IL-9 locus via recruiting histone acetyltransferases [38,58].”
BackgroundIL-9 Regulates Allergen-Specific Th1 Responses in Allergic Contact Dermatitis
Liu, J., Harberts, E. M., Tammaro, A., Girardi, N. G., Filler, R. B., Fishelevich, R., Temann, U.-A., Licona-Limón, P., Girardi, M., Flavell, R. A., et al. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.61 · Cited by 83 · see citing works
“We also studied Th9associated transcription factors PU.1, ETS-1, IRF-4 and GcN5 (Oikawa and Yamada 2003, Refaat et al, 2011, Goswami and Kaplan, 2012) which were all similarly elevated 2 to 3 (range 1.5–8)-fold higher than paired control skin (Figure 1B).”
BackgroundInfluentialThe transcription factor network in Th9 cells
Kaplan, M. H. (2016) · Seminars in Immunopathology · doi:10.1007/s00281-016-0600-2 · Cited by 81 · see citing works
Self-citationTh9 Cells: A Novel CD4 T-cell Subset in the Immune War against Cancer
Végran, F., Apétoh, L., & Ghiringhelli, F. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2748 · Cited by 77 · see citing works
Th9 Cell Differentiation and Its Dual Effects in Tumor Development
Chen, T., Guo, J., Cai, Z., Li, B., Sun, L., Shen, Y., Wang, S., Wang, Z., Wang, Z., Wang, Y., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01026 · Cited by 69 · see citing works
“Hence, the binding to other transcription factors was facilitated and the transcription of the Il9 gene was initiated (63).”
BackgroundNitric oxide enhances Th9 cell differentiation and airway inflammation
Niedbała, W., Besnard, A., Nascimento, D. C., Donate, P. B., Sônego, F., Yip, E., Guabiraba, R., Chang, H., Fukada, S. Y., Salmond, R. J., et al. (2014) · Nature Communications · doi:10.1038/ncomms5575 · Cited by 68 · see citing works
IRF8‐dependent Molecular Complexes Control the Th9 Transcriptional Program
Humblin, E., Thibaudin, M., Chalmin, F., Derangère, V., Limagne, E., Richard, C., Flavell, R. A., Chevrier, S., Ladoire, S., Berger, H., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01070-w · Cited by 67 · see citing works
Bi, E., Ma, X., Lu, Y., Yang, M., Wang, Q., Xue, G., Qian, J., Wang, S., & Yi, Q. (2017) · Science Signaling · doi:10.1126/scisignal.aak9741 · Cited by 64 · see citing works
T Helper 9 Cells: A New Player in Immune-Related Diseases
Chen, J., Guan, L., Tang, L., Liu, S., Zhou, Y., Chen, C., He, Z., & Xu, L. (2019) · DNA and Cell Biology · doi:10.1089/dna.2019.4729 · Cited by 62 · see citing works
Koh, B., Hufford, M. M., Pham, D., Olson, M. R., Wu, T., Jabeen, R., Sun, X., & Kaplan, M. H. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502383 · Cited by 49 · see citing works
“1-deficient Th9 cells that had increased p300 association and decreased Gcn5 association with the Il9 locus (9), ETV5-deficient cells had normal Gcn5 recruitment but”
BackgroundInfluentialSelf-citationThe Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation
Gao, B., Kong, Q., Zhang, Y., Yun, C., Dent, S., Song, J. J., Zhang, D. D., Wang, Y., Li, X., & Fang, D. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1600312 · Cited by 51 · see citing works
“Although NFAT acetylation has not been reported, Gcn5-mediated acetylation of transcription factors such as NF-kB often enhances their transcriptional activity (12, 14, 19, 39), so we analyzed whether Gcn5 catalyzes NFAT1 acetylation to promote il-2 gene transcription in T cells.”
BackgroundDetection of IL-9 producing T cells in the PBMCs of allergic asthmatic patients
Jia, L., Wang, Y., Li, J., Li, S., Zhang, Y., Shen, J., Tan, W., & Wu, C. Y. (2017) · BMC Immunology · doi:10.1186/s12865-017-0220-1 · Cited by 49 · see citing works
“1 directly binds to Il9 locus and initiates the downstream genetic modification to enhance the production of IL-9 [26, 27].”
T cell receptor signaling in the differentiation and plasticity of CD4+ T cells
Meitei, H. T., & Lal, G. (2022) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2022.08.001 · Cited by 49 · see citing works
Singh, Y., Garden, O. A., Lang, F., & Cobb, B. S. (2016) · Immunology · doi:10.1111/imm.12631 · Cited by 37 · see citing works
IL-9 signaling as key driver of chronic inflammation in mucosal immunity
Neurath, M. F., & Finotto, S. (2016) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2016.02.002 · Cited by 42 · see citing works
Carrascosa, L. C., Klein, M., Kitagawa, Y., Lückel, C., Marini, F., König, A., Guralnik, A., Raifer, H., Hagner-Benes, S., Raedler, D., et al. (2017) · Nature Communications · doi:10.1038/ncomms15366 · Cited by 41 · see citing works
PU.1 Suppresses Th2 Cytokine Expression via Silencing of GATA3 Transcription in Dendritic Cells
Yashiro, T., Kubo, M., Ogawa, H., Okumura, K., & Nishiyama, C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137699 · Cited by 41 · see citing works
“1 is required for chromatin modification of the IL-9 promoter in a Th subtype-specific manner, resulting in the expression of IL-9 in Th9 cells [37].”
BackgroundToll like Receptor 2 engagement on CD4+ T cells promotes TH9 differentiation and function
Karim, A. F., Reba, S. M., Li, Q., Boom, W. H., & Rojas, R. E. (2017) · European Journal of Immunology · doi:10.1002/eji.201646846 · Cited by 41 · see citing works
Pajulas, A., Zhang, J., & Kaplan, M. H. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2300094 · Cited by 40 · see citing works
Self-citationDifferentiation, Regulation and Function of Th9 Cells
Jia, L., & Wu, C. Y. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-94-017-9487-9_7 · Cited by 38 · see citing works
The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation
Wang, Y., Yun, C., Gao, B., Xu, Y., Zhang, Y., Wang, Y., Kong, Q., Zhao, F., Wang, C.-R., Dent, S., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.065 · Cited by 40 · see citing works
“Goswami R, Kaplan MH. Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells.”
BackgroundTranscriptional regulation of CD4+ TH cells that mediate tissue inflammation
Loo, T. T., Gao, Y., & Lazarevic, V. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.1ri0418-152rr · Cited by 42 · see citing works
Epigenetic Alterations in Cellular Immunity: New Insights into Autoimmune Diseases
Wang, Z., Lu, Q., & Wang, Z. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000457944 · Cited by 40 · see citing works
Regulation of T cell differentiation and function by epigenetic modification enzymes
Liu, H., Li, P., Wei, Z., Zhang, C., Xia, M., Du, Q., Chen, Y., Liu, N., Li, H., & Yang, X. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00731-w · Cited by 37 · see citing works
Effect of vitamin D on T-helper type 9 polarized human memory cells in chronic persistent asthma
Keating, P., Munim, A., & Hartmann, J. X. (2013) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2013.11.015 · Cited by 34 · see citing works
A conserved enhancer regulates Il9 expression in multiple lineages
Koh, B., Qayum, A. A., Srivastava, R., Fu, Y., Ulrich, B. J., Janga, S. C., & Kaplan, M. H. (2018) · Nature Communications · doi:10.1038/s41467-018-07202-0 · Cited by 34 · see citing works
Self-citationT cells and their function in the immune response to viruses
Beňová, K., Hancková, M., Koči, K., Kúdelová, M., & Betáková, T. (2020) · Acta Virologica · doi:10.4149/av_2020_203 · Cited by 34 · see citing works
Vyas, S., Hansda, A. K., Kaplan, M. H., & Goswami, R. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901205 · Cited by 32 · see citing works
“Several studies suggest that HDAC1/2 inhibitors such as TSA can reverse the repressive chromatin at the Il9 gene locus and thereby rescue Foxp3-mediated suppression of Il9 gene transcription (33, 35).”
BackgroundSelf-citationTranscriptional Programs Underlying Cd4 T Cell Differentiation and Functions
Chalmin, F., Humblin, É., Ghiringhelli, F., & Végran, F. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.07.002 · Cited by 31 · see citing works
ETS Transcription Factors in Immune Cells and Immune-Related Diseases
Yang, Y., Han, X., Sun, L., Shao, F., Yin, Y., & Zhang, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251810004 · Cited by 34 · see citing works
“PU.1 increases histone acetylation at the IL-9 sites through direct interaction with histone acetyltransferases, thereby promoting IL-9 expression [28].”
BackgroundEpigenetic dynamics during CD4+ T cells lineage commitment
Rodríguez, R. M. A., López‐Larrea, C., & Suárez-Álvarez, B. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.04.020 · Cited by 28 · see citing works
Awe, O., Hufford, M. M., Wu, H., Pham, D., Chang, H.-C., Jabeen, R., Dent, A. L., & Kaplan, M. H. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500780 · Cited by 27 · see citing works
“1 is expressed in mature peripheral T cells and expression is induced by T cell activation and culture of T cells with specific cytokines, including the cytokines that promote Treg, Th9 and Th2 development (4, 22-25).”
BackgroundMethodSelf-citationTh9 lymphocytes: A recent history from IL-9 to its potential role in rheumatic diseases
Rojas-Zuleta, W. G., & Vásquez, G. M. (2016) · Autoimmunity Reviews · doi:10.1016/j.autrev.2016.02.020 · Cited by 27 · see citing works
Signatures of DNA target selectivity by ETS transcription factors
Poon, G. M. K., & Kim, H. M. (2017) · Transcription · doi:10.1080/21541264.2017.1302901 · Cited by 27 · see citing works
“1 as a strong pioneer transcription factor,(63) by anchoring target genes in chromatin during recruitment of other transcription factors and remodeling proteins (such as histone acetyltransferases).(64) Currently, the pioneer status of Ets-1 is controversial: Although it appears to co-localize with nucleosomes in enha…”
BackgroundLi, Y., Yu, Q., Zhang, Z., Wang, J., Li, S., Zhang, J., & Liu, G. (2016) · Oncotarget · doi:10.18632/oncotarget.11681 · Cited by 23 · see citing works
“1 [21, 38, 39], IRF1 [28], IRF4 [40], NF-kB [41], Bcl6 [42], and the Smad/Notch complex [43], directly interact with the Il9 gene promoter to increase IL-9 production (Figure 2).”
BackgroundDifferentiation and regulation of CD4+ T cell subsets in Parkinson’s disease
Sun, X., Gu, R., & Bai, J. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05402-0 · Cited by 22 · see citing works
“…induces the expression of the signature tran - scription factor PU.1 in Th9 cells, which promotes their differentiation by interfering with GATA-3 expression [ 65] or affecting chromatin modification through binding to the IL-9 promoter [ 66 ], as well as inhibits Th2 cells differentia - tion (Fig.”
BackgroundIL-9-producing Th9 cells may participate in pathogenesis of Takayasu’s arteritis
Pan, L., Du, J., Gao, N., et al. (2016) · Clinical Rheumatology · doi:10.1007/s10067-016-3399-2 · Cited by 23 · see citing works
“1 is the key transcription factor that determines the development of Th9 cells [26].”
BackgroundRole of Ets Proteins in Development, Differentiation, and Function of T‐Cell Subsets
Liu, M., Gao, W., van Velkinburgh, J. C., Wu, Y., Ni, B., & Tian, Y. (2015) · Medicinal Research Reviews · doi:10.1002/med.21361 · Cited by 20 · see citing works
Metabolism in Immune Cell Differentiation and Function
Chapman, N. M., Shrestha, S., & Chi, H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-94-024-1170-6_1 · Cited by 20 · see citing works
Tuxun, T., Apaer, S., Ma, H.-Z., Zhang, H., Aierken, A., Lin, R., & Wen, H. (2015) · Journal of Immunology Research · doi:10.1155/2015/895416 · Cited by 18 · see citing works
Zhang, Y., Siegel, A., Sun, G., DiMaggio, T., Freeman, A. F., & Milner, J. D. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.06.036 · Cited by 18 · see citing works
Sheng, Y., Zhang, J., Li, K., Wang, H., Wang, W., Wen, L., Gao, J., Tang, X., Tang, H., Huang, H., et al. (2020) · FEBS Open Bio · doi:10.1002/2211-5463.13050 · Cited by 16 · see citing works
RetractedEffect of Th9/IL-9 on the growth of gastric cancer in nude mice
Li, C., Zhang, Y., Zhang, Y., Chen, H., & Hu, J. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s197816 · Cited by 18 · see citing works
“1 enhances gene transcription through recruiting histone acetyltransferases (HATs) and enhancing permissive chromatin structure, and therefore control the functional maturation of the immune system.(31) P53 and p21 are tumor suppressor proteins that regulate the expression of a wide variety of genes, including apoptos…”
BackgroundDynamics of Th9 cells and their potential role in immunopathogenesis of murine schistosomiasis
Zhan, T., Zhang, T., Wang, Y., Wang, X., Lin, C., Ma, H., Duan, Z., Li, C., Xu, J., & Xia, C.-M. (2017) · Parasites & Vectors · doi:10.1186/s13071-017-2242-1 · Cited by 16 · see citing works
“1 is a key transcription factor for the differentiation of Th9 cells [22].”
Abdelaziz, M. H., Wang, H., Cheng, J., & Xu, H. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8420 · Cited by 17 · see citing works
Zheng, R., Qian, L., Yu, J., et al. (2017) · Biomedical Reports · doi:10.3892/br.2017.904 · Cited by 15 · see citing works
“PU.1 is a transcription factor implicated in the regulation of Th9 cells function by directly binding to IL-9 loci (17).”
Lee, W. H., Hong, K. J., Li, H., & Lee, G. R. (2023) · Advanced Science · doi:10.1002/advs.202305527 · Cited by 15 · see citing works
Inaba, K., Yashiro, T., Hiroki, I., Watanabe, R., Kasakura, K., & Nishiyama, C. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901008 · Cited by 13 · see citing works
Locus of (IL-9) control: IL9 epigenetic regulation in cellular function and human disease
Son, A., Baral, I., Falduto, G. H., & Schwartz, D. M. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01241-y · Cited by 12 · see citing works
“2) 30 .”
Regulatory role of T helper 9/interleukin-9: Transplantation view
Roostaee, A., Yaghobi, R., Afshari, A., & Jafarinia, M. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e26359 · Cited by 10 · see citing works
“In Th9 cells, PU.1 binds to the promoter of the Il-9 gene to promote Th9 cell polarization [68].”
BackgroundKharwadkar, R. P., Ulrich, B. J., Chu, M., Koh, B., Hufford, M. M., Fu, Y., Birdsey, G. M., Porse, B. T., RANDI, A. M., & Kaplan, M. H. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200113 · Cited by 11 · see citing works
Self-citationCalcitriol and Retinoic acid antagonize each other to suppress the production of IL-9 by Th9 cells
Vyas, S., & Goswami, R. (2021) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2021.108788 · Cited by 9 · see citing works
Self-citationMallon, S., Wakim, B. T., & Roizman, B. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218783109 · Cited by 9 · see citing works
“Transcription factor (51, 52) 0/7 5 Q86WZ6 ZNF227 Unknown.”
Végran, F., Martin, F., Apétoh, L., & Ghiringhelli, F. (2016) · médecine/sciences · doi:10.1051/medsci/20163204017 · Cited by 9 · see citing works
Neobavaisoflavone-mediated TH9 cell differentiation ameliorates bowel inflammation
Guo, J., Qiao, C., Zhou, J., Hu, S., Lin, X., Shen, Y., Li, Z., & Liu, J. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108191 · Cited by 9 · see citing works
Th9 Cells: New Member of T Helper Cell Family
Goswami, R. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6877-0_1 · Cited by 7 · see citing works
Self-citationAskari, A. A., Feizollahi, P., Rezaiemanesh, A., Salari, F., & Karaji, A. G. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e08556 · Cited by 6 · see citing works
Targeting Th9 cells in autoimmune diseases: a narrative review
Xu, W., Chen, Y., Li, Y.-W., Yang, J., & Huang, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1615611 · Cited by 5 · see citing works
“WT Th9 cells transfected with a PU.1-overexpression vector showed an increased frequency of CD4 + IL-9 + T cells, a reduced IL-4 expression, and an enhanced recruitment of GCN5 to the IL-9 gene promoter (25).”
Khokhar, M., Purohit, P., Gadwal, A., Bajpai, N. K., & Shukla, R. K. G. (2025) · International Reviews of Immunology · doi:10.1080/08830185.2025.2515836 · Cited by 5 · see citing works
“Th9 cells can induce IL-9 expression with IL-4 and TGF-β, and IL-9 has been studied for its potential therapeutic use in various diseases [15,16].”
Ohnmacht, C., & Eyerich, S. (2021) · Handbook of experimental pharmacology · doi:10.1007/164_2021_486 · Cited by 5 · see citing works
Jang, Y. W., Gil, K. C., Lee, J. S., Kang, W., Park, S., & Hwang, K. W. (2019) · Bioelectromagnetics · doi:10.1002/bem.22219 · Cited by 4 · see citing works
Regulatory mechanisms of Th9 cell differentiation
Liu, X., Li, Y., Wu, W., Huang, H., Hao, Y., & Song, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1650972 · Cited by 3 · see citing works
“Furthermore, PU.1 has been shown to form a complex with the histone acetyltransferase General Control Non-derepressible 5 (GCN5), which increases histone H3/H4 acetylation levels in the IL-9 promoter region, thereby markedly increasing transcriptional activity and chromatin accessibility (21, 82).”
New insights into Th9 cells in inflammatory bowel diseases
Neurath, M. F. (2025) · Seminars in Immunology · doi:10.1016/j.smim.2025.102013 · Cited by 3 · see citing works
Liang, M., Zhang, Y., Wang, M., Wen, Z., Cheng, C., Bu, Y., Lu, M., Song, X., Xu, L., Li, X., et al. (2023) · Veterinary Research · doi:10.1186/s13567-023-01214-5 · Cited by 3 · see citing works
“…directly binding to the Il9 locus and recruiting Gcn5 [Kat2a, K(lysine) acetyltransferase 2A] and PCAF [Kat2b, K(lysine) acetyltransferase 2B] [32, 33], resulting in the formation of open chromatin at the Il9 locus and promoting the binding of transcription factors such as IRF4 for Il9 gene…”
BackgroundTh9/ IL ‐9 may participate in the pathogenesis of multiple myeloma
Liu, Y., Xie, Y.-H., Han, X., Li, P., Zhou, J., Hu, X., & Wang, Q. (2023) · International Journal of Laboratory Hematology · doi:10.1111/ijlh.14210 · Cited by 3 · see citing works
“33,34 Research conducted earlier has revealed that the transcription factor IRF4 regulates the IL-9's expression and contributes to the formation of Th9 cells.”
BackgroundShafi, T., Rasool, R., Bhat, R., Ayub, S., Gull, A., Rashid, I., & Koul, A. M. (2025) · Immunologic Research · doi:10.1007/s12026-025-09671-0 · Cited by 2 · see citing works
T Cells and Their Subsets in Autoimmunity
Burkett, P. R., Pawlak, M., Peters, A., & Kuchroo, V. K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812102-3.00006-3 · Cited by 2 · see citing works
Roles of Menin in T cell differentiation and function: Current knowledge and perspectives
Zhou, P., Liu, W., & Ma, J. (2024) · Immunology · doi:10.1111/imm.13837 · Cited by 1 · see citing works
“Little is known about the transcriptional regulation of PU.1 expression [85], making it difficult to predict whether and how Menin regulates PU.1 expression during Th9 differentiation.”
Kadhom, M. K., Hatem, R. M., & Mohammed, K. I. (2025) · Human Antibodies · doi:10.1177/10932607251349046 · Cited by 1 · see citing works
“16 In addition, complex dynamics between cytokines are demonstrated by the interaction between IL-9 and IFN-γ in allergic asthma.”
Novel therapeutic strategies leveraging TH9 cell anticancer functions
Xu, J., Abdoul‐Azize, S., & Apétoh, L. (2026) · Seminars in Immunology · doi:10.1016/j.smim.2026.102026 · Cited by 1 · see citing works
Afrough, N., Soltani, A., Khosravi, M., Yadollahi, N., Khodadadi, A., & Shohan, M. (2026) · Inflammation and Regeneration · doi:10.1186/s41232-026-00423-7 · Cited by 1 · see citing works
“It directly binds to IL-9 promoter, recruits histone acetyltransferases like Gcn5, and regulates chromatin remodeling [84].”
Homeobox Transcription Factor HOXB4 Distinctly Modulates Th2 and Th9 Cell Differentiation
Chattopadhyay, S., Hazra, S., Biswas, B. K., & Goswami, R. (2025) · European Journal of Immunology · doi:10.1002/eji.202451752 · Cited by 1 · see citing works
Self-citationT H 9 Cells in Immunity and Disease
Chang, H., & Kaplan, M. H. (2015) · Wiley eBooks · doi:10.1002/9780470015902.a0026234
Self-citationA Subset Apart? Th9 cell regulation and current limitations to study
Zheng, Z., & Kang, J. (2015) · Journal of nature and science
Th9 Cells: From the Bench to the Bedside and Back Again
Ulrich, B. J., Hufford, M. M., & Kaplan, M. H. (2017) · Wiley-VCH eBooks · doi:10.1002/9783527692156.ch15
Self-citationAlsiary, R., Katouah, H. A., Al-Amodi, H. S. A. B., & Al-Toub, M. (2023) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9789815080384123010007
Haemonchus contortus HcL6 promoted goat Th9 immune response by activation STAT6/PU.1/NF-κB PathwayPreprint
Liang, M., Zhang, Y., Wang, M., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-3105776/v1
Transcription factors in the development of Th9 cells
Goswami, R. (2013) · ProQuest Demo Repository · doi:10.7912/c2/1714
Self-citation
- Authors
- Goswami, R., & Kaplan, M. H.
- Affiliations
- Indiana University Indianapolis (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-09
- Volume
- 189
- Issue
- 6
- Pages
- 3026-3033
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3436945
- OpenAlex
- W1526182144
- Cited by
- 97
- References
- 50
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 1 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 15 · 2016: 9 · 2015: 9 · 2014: 6 · 2013: 8 · 2012: 1
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- 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 › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- GCN5, PU.1, Th9 cells, IL-9, histone acetylation, histone deacetylase, histone acetyltransferase, PCAF
- MeSH terms
- p300-CBP-Associated Factor, Proto-Oncogene Protein Spi-1, Acetylation, Animals, Cells, Cultured, Female, T-Lymphocytes, Helper-Inducer, Histone Deacetylases
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 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
