Polycomb Antagonizes p300/CREB-binding Protein-associated Factor to Silence FOXP3 in a Kruppel-like Factor-dependent Manner

Xiong, Yuning; Khanna, Sahil; Grzenda, Adrienne; Sarmento, Olga F.; Svingen, Phyllis A.; Lomberk, Gwen; Urrutia, Raúl; Faubion, William A.

doi:10.1074/jbc.m111.325332

Cited by 54 publications

(81 citation statements)

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“…We propose that KLF2 is incorporated into a signaling complex that provides transcriptional accessibility to the entire FoxP3 locus, after which additional nuclear factors stabilize the open conformation in a KLF2-independent manner. Consistent with a previous report (38), this larger signaling complex may include histone acetyltransferases that reverse p300/CBP-associated factor-mediated FoxP3 gene silencing in naïve CD4 + T cells. Importantly, we demonstrate that KLF2 is a rate-limiting factor during this inductive process that can be targeted with drugs to enhance iTreg production via increased KLF2 stability.…”

Section: Discussionsupporting

confidence: 90%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T cells (Tregs) are a specialized subset of CD4 + T cells that maintain self-tolerance by functionally suppressing autoreactive lymphocytes. The Treg compartment is composed of thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs) that are generated in secondary lymphoid organs after exposure to antigen and specific cytokines, such as TGF-β. With regard to this latter lineage, pTregs [and their ex vivo generated counterparts, induced Tregs (iTregs)] offer particular therapeutic potential because these cells can be raised against specific antigens to limit autoimmunity. We now report that transcription factor Krüppel-like factor 2 (KLF2) is necessary for the generation of iTregs but not tTregs. Moreover, drugs that limit KLF2 proteolysis during T-cell activation enhance iTreg development. To the authors' knowledge, this study identifies the first transcription factor to distinguish between i/pTreg and tTreg ontogeny and demonstrates that KLF2 is a therapeutic target for the production of regulatory T cells.

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Section: Discussionsupporting

confidence: 90%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…More relevant to the current study, recent reports have identified a role for KLF10 in T lymphocytes and innate immune cells (21,28). We have previously shown that the genetic inactivation of KLF10 epigenetically silences FOXP3 via EZH2 (enhancer of zeste 2)-mediated trimethylation of histone 3 K27, resulting in an impaired induction of this gene with a concomitant inappropriate adaptive T regulatory (Treg) cell differentiation in vitro and in vivo (23).…”

mentioning

confidence: 82%

“…Chromatin immunoprecipitation assays (ChIP) assays were performed as previously described (23). Two million murine CAR-expressing CD8 ϩ T cells were transfected with KLF10-His adenovirus or empty vector.…”

Section: Murine Cd8mentioning

confidence: 99%

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Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8⁺ T lymphocytes

Papadakis

Krempski

Reiter

et al. 2015

American Journal of Physiology-Cell Physiology

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KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-β1 (TGF-β1) signaling in CD4+ T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-β receptor II (TGF-βRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8+ T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10−/− CD8+ T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8+ T cells from the spleen of adult mice express lower levels of surface TGF-βRII (TβRII). Congruently, in vitro activation of KLF10-deficient CD8+ T cells upregulate TGF-βRII to a lesser extent compared with wild-type (WT) CD8+ T cells, which results in attenuated Smad2 phosphorylation following TGF-β1 stimulation compared with WT CD8+ T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-βRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-βRII among viral-specific KLF10−/− CD8+ T cells and a higher percentage of IFN-γ-producing CD8+ T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-βRII in CD8+ T cells. Thus, KLF10 regulation of TGF-βRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-β1/TGF-βRII signaling pathway is crucial.

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“…These cells are defined by the expression of the lineage-specific expression of the transcription factor Forkhead Box P3 (FOXP3) [15]. Dr. Faubion’s group and others have shown that FOXP3 recruits EZH2 to repress gene expression [16,17]. Transgenic mouse studies in which the EZH2 SET domain (which carries the methyltransferase activity of EZH2) was deleted in FOXP3+ cells demonstrated that Ezh2 ΔSET/ΔSET -Tregs did not show a regulator phenotype and secreted proinflammatory cytokines, unlike Tregs from Ezh2 +/+ mice.…”

Section: Epigenetic Dynamics In Non-neoplatic Diseasesmentioning

confidence: 99%

Epigenetics of gastrointestinal diseases: notes from a workshop

et al. 2018

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International experts gathered at the Mayo Clinic (Rochester MN, USA) on February 27th-28th, 2017 for a meeting entitled ‘Basic and Translational Facets of the Epigenetics of GI Diseases’. This workshop summarized recent advances on the role of epigenetics in the pathobiology of gastrointestinal (GI) diseases. Highlights of the meeting included recent advances on the involvement of different epigenetic mechanisms in malignant and nonmalignant GI disorders and the epigenetic heterogeneity exhibited in these diseases. The translational value of epigenetic drugs, as well as the current and future use of epigenetic changes (i.e., DNA methylation patterns) as biomarkers for early detection tools or disease stratification were also important topics of discussion.

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Polycomb Antagonizes p300/CREB-binding Protein-associated Factor to Silence FOXP3 in a Kruppel-like Factor-dependent Manner

Cited by 54 publications

References 54 publications

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8⁺ T lymphocytes

Epigenetics of gastrointestinal diseases: notes from a workshop

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Polycomb Antagonizes p300/CREB-binding Protein-associated Factor to Silence FOXP3 in a Kruppel-like Factor-dependent Manner

Cited by 54 publications

References 54 publications

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes

Epigenetics of gastrointestinal diseases: notes from a workshop

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Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8⁺ T lymphocytes