FoxP3 interacts with linker histone H1.5 to modulate gene expression and program Treg cell activity

Mackey-Cushman, Stephanie; Gao, Jianmei; Holmes, Derek A; Nunoya, Jun-ichi; Wang, Rui; Unutmaz, Derya; Su, Lishan

doi:10.1038/gene.2011.31

Cited by 30 publications

(31 citation statements)

References 31 publications

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“…Its Ume6-dependent recruitment to early meiotic genes supports a growing body of evidence that linker histones, although ubiquitous throughout the genome, may play specific roles in the repression of related genes via transcription factor recruitment (10,33,37,48,52). In addition, Hho1 plays a role in genome compaction specifically in the late stages of sporulation.…”

Section: Discussionmentioning

confidence: 71%

“…The linker histone represses transcription in vitro, but its transcriptional role in vivo has been the subject of debate (7,24). Although H1 has historically been associated with chromatin compaction and general repression, several recent studies have implicated the linker histone in the repression of specific genes via recruitment by transcription factors (10,33,37,45,48,52).…”

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confidence: 99%

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The Linker Histone Plays a Dual Role during Gametogenesis in Saccharomyces cerevisiae

Bryant

Govin

Zhang

et al. 2012

Molecular and Cellular Biology

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fThe differentiation of gametes involves dramatic changes to chromatin, affecting transcription, meiosis, and cell morphology. Sporulation in Saccharomyces cerevisiae shares many chromatin features with spermatogenesis, including a 10-fold compaction of the nucleus. To identify new proteins involved in spore nuclear organization, we purified chromatin from mature spores and discovered a significant enrichment of the linker histone (Hho1). The function of Hho1 has proven to be elusive during vegetative growth, but here we demonstrate its requirement for efficient sporulation and full compaction of the spore genome. Hho1 chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed increased genome-wide binding in mature spores and provides novel in vivo evidence of the linker histone binding to nucleosomal linker DNA. We also link Hho1 function to the transcription factor Ume6, the master repressor of early meiotic genes. Hho1 and Ume6 are depleted during meiosis, and analysis of published ChIP-chip data obtained during vegetative growth reveals a high binding correlation of both proteins at promoters of early meiotic genes. Moreover, Ume6 promotes binding of Hho1 to meiotic gene promoters. Thus, Hho1 may play a dual role during sporulation: Hho1 and Ume6 depletion facilitates the onset of meiosis via activation of Ume6-repressed early meiotic genes, whereas Hho1 enrichment in mature spores contributes to spore genome compaction. Gametogenesis is a complex, highly regulated differentiation program that is integral to the survival of higher eukaryotes. Mammalian spermatogenesis begins with DNA replication and recombination, ultimately generating four genetically unique haploid cells. The postmeiotic differentiation of spermatozoa involves a complete reorganization of the chromatin and a dramatic compaction of the nucleus that prepare the genome for passage to a new generation (16,30). In fact, specific combinations of histone posttranslational modifications (PTMs) are found at genes encoding important developmental regulators (5,20).Gametogenesis in Saccharomyces cerevisiae, or sporulation, shares several chromatin features with mammalian spermatogenesis, namely, drastic compaction of the nucleus and stage-specific appearance of histone PTMs such as phosphorylation of histone H3 at serine 10 (H3S10ph), H3T11ph, and H4S1ph (17, 31). Sporulation takes place in diploid yeast deprived of nitrogen and a fermentable carbon source (15,39). Under these starvation conditions, yeast cells enter a meiotic program similar to that found in mammalian spermatogenesis. During the postmeiotic phase, cell and nuclear volumes are substantially decreased, the genome is compacted, transcription is silenced, and a protective spore wall is synthesized. The resultant quiescent spore is able to survive unfavorable growth conditions of heat, dehydration, and chemical insult. When a fermentable carbon source is reintroduced, spores are induced to reenter the cell cycle through a process called germination, characterized by a spec...

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

The Linker Histone Plays a Dual Role during Gametogenesis in Saccharomyces cerevisiae

Bryant

Govin

Zhang

et al. 2012

Molecular and Cellular Biology

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“…This may be achieved through interaction with tissue-specific transcription factors to regulate specific genes during infection. A similar mechanism may exist in human CD4 ϩ CD25 ϩ regulatory T (Treg) cells, where the forkhead transcription factor FoxP3 interacts with linker histone H1.5 to modulate interleukin-2 (IL-2) gene expression in the Treg cells (32). To summarize, it appears that H1 histones, including their variants and associated posttranslational modifications, in conjunction with their reader molecules, have a more specialized function than initially presumed.…”

Section: Discussionmentioning

confidence: 95%

Novel Roles of Caenorhabditis elegans Heterochromatin Protein HP1 and Linker Histone in the Regulation of Innate Immune Gene Expression

Studencka

Konzer

Moneron

et al. 2012

Molecular and Cellular Biology

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Linker histone (H1) and heterochromatin protein 1 (HP1) are essential components of heterochromatin which contribute to the transcriptional repression of genes. It has been shown that the methylation mark of vertebrate histone H1 is specifically recognized by the chromodomain of HP1. However, the exact biological role of linker histone binding to HP1 has not been determined. Here, we investigate the function of the Caenorhabditis elegans H1 variant HIS-24 and the HP1-like proteins HPL-1 and HPL-2 in the cooperative transcriptional regulation of immune-relevant genes. We provide the first evidence that HPL-1 interacts with HIS-24 monomethylated at lysine 14 (HIS-24K14me1) and associates in vivo with promoters of genes involved in antimicrobial response. We also report an increase in overall cellular levels and alterations in the distribution of HIS-24K14me1 after infection with pathogenic bacteria. HIS-24K14me1 localization changes from being mostly nuclear to both nuclear and cytoplasmic in the intestinal cells of infected animals. Our results highlight an antimicrobial role of HIS-24K14me1 and suggest a functional link between epigenetic regulation by an HP1/H1 complex and the innate immune system in C. elegans.

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“…1,2 The molecular mechanisms of FOXP3-mediated regulation of gene transcription are not clearly defined, but repression involves interactions with the histone acetyl-transferase TIP60, the histone deacetylase HDAC7, and linker histone H1.5. 3,4 After its discovery in Tregs, it was soon demonstrated that FOXP3 is also expressed transiently in human Tconv cells after TCR activation. [5][6][7][8][9][10][11] Similarly, another Treg-associated transcription factor, Helios, can also be expressed on activation.…”

Section: Introductionmentioning

confidence: 99%

A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells

McMurchy

Gillies

Gizzi

et al. 2013

Blood

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Key Points• FOXP3 functions as a negative regulator of T-cell proliferation and cytokine production in human conventional T cells.• Expression of FOXP3 in human Th17 cells functions to suppress IFN-␥ production. IntroductionExpression of the transcription factor forkhead box P3 (FOXP3) in T-regulatory cells (Tregs) is necessary and sufficient for Tregs to suppress the effector function of conventional T (Tconv) cells. In cooperation with other transcription factors, including NFAT and Runx1, and the Th17-associated transcription factors ROR-␥t and ROR␣, FOXP3 establishes the Treg program by repressing or trans-activating defined genes. 1,2 The molecular mechanisms of FOXP3-mediated regulation of gene transcription are not clearly defined, but repression involves interactions with the histone acetyl-transferase TIP60, the histone deacetylase HDAC7, and linker histone H1.5. 3,4 After its discovery in Tregs, it was soon demonstrated that FOXP3 is also expressed transiently in human Tconv cells after TCR activation. [5][6][7][8][9][10][11] Similarly, another Treg-associated transcription factor, Helios, can also be expressed on activation. 12 The major differences between FOXP3 in Tregs and Tconv cells are in stability and expression levels. In Tregs, the Treg-specific demethylated region (TSDR) region of the FOXP3 promoter is demethylated, permitting high and stable expression. 13 Conversely, in Tconv cells, the TSDR is methylated, resulting in transient expression of FOXP3 that never reaches the intensity of that in similarly activated Tregs. 6,7,9,13 Transient FOXP3 expression in Tconv cells does not prevent cytokine production and/or confer suppressive capacity, although this has been a point of controversy. [5][6][7][8][9][10][11] Another role for FOXP3 is to antagonize Th17 cell development. Interaction of FOXP3 with ROR-␥t or Runx1 inhibits IL-17 production, 1 whereas ROR-␥t together with hypoxia-inducible factor 1␣ inhibits FOXP3. 14 Therefore, in a tolerogenic environment that includes TGF␤, FOXP3 suppresses Th17 cell development and Treg differentiation prevails. In contrast, in inflammatory environments hypoxia inducible factor1␣ promotes ROR-␥t expression, causing degradation of FOXP3, promotion of Th17 cell development, and blockade of Treg differentiation. 14 Beyond this "tug-of-war" during differentiation, Tregs and Th17 cells may have the ability to interconvert. FOXP3 ϩ IL-17-secreting cells exist in vivo, 15-17 but it is not clear whether these cells are Tregs that have begun to secrete IL-17 or if they are Th17 cells that have begun to express FOXP3.Despite clear evidence that FOXP3 is expressed in Tconv cells, its function remained unknown. In the present study, we investigated the role of FOXP3 in human Tconv cells and found that FOXP3-deficient Tconv cells proliferated to a greater extent and produced greater amounts of cytokines than wild-type (WT) Tconv cells. Furthermore, FOXP3 was highly expressed in activated Th17 The online version of this article contains a data supplement.The publicati...

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FoxP3 interacts with linker histone H1.5 to modulate gene expression and program Treg cell activity

Cited by 30 publications

References 31 publications

The Linker Histone Plays a Dual Role during Gametogenesis in Saccharomyces cerevisiae

The Linker Histone Plays a Dual Role during Gametogenesis in Saccharomyces cerevisiae

Novel Roles of Caenorhabditis elegans Heterochromatin Protein HP1 and Linker Histone in the Regulation of Innate Immune Gene Expression

A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells

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