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UTX controls lineage-specific epigenetic program of iNKT cells

ABSTRACT: NKT cells are innate-like lymphocytes that protect against infection, autoimmune disease, and cancer. However, little is known about epigenetic regulation of iNKT cell development. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibit impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. Notably, we identified JunB as a novel regulator of iNKT development that partners with UTX to establish an iNKT lineage specific gene expression program. Moreover, we demonstrate that UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment. These findings uncover how UTX regulates iNKT cell development through multiple epigenetic mechanisms.

ORGANISM(S): Mus musculus

PROVIDER: GSE84238 | GEO | 2016/07/12

SECONDARY ACCESSION(S): PRJNA328452

REPOSITORIES: GEO

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UTX controls lineage-specific epigenetic program of iNKT cells

Project description:iNKT cells are innate-like lymphocytes that protect against infection, autoimmune disease, and cancer. However, little is known about epigenetic regulation of iNKT cell development. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX deficient iNKT cells exhibit impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. Notably, we identified JunB as a novel regulator of iNKT development that partners with UTX to establish an iNKT lineage specific gene expression program. Moreover, we demonstrate that UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment. These findings uncover how UTX regulates iNKT cell development through multiple epigenetic mechanisms.

2016-12-19 | GSE84015 | GEO

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq]

Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naM-CM-/ve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage. H3K27me3 and H3K4me3 were measured genome-wide in the following cell types: Utx+/Y (WT) and Utx-/Y (KO) mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors).

2012-05-30 | E-GEOD-37821 | biostudies-arrayexpress

The X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex specific manner

Project description:This SuperSeries is composed of the following subset Series: GSE39472: X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner [ChIP-Seq data] GSE39473: The X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex specific manner [Agilent array data] Refer to individual Series

2012-07-31 | E-GEOD-39222 | biostudies-arrayexpress

Histone Demethylase UTX-1 Regulates the Caenorhabditis elegans Lifespan by Targeting the Insulin/IGF-1 Signaling Pathway

Project description:Epigenetic modifications are thought to be important for gene expression changes during development and aging. However, besides the Sir2 histone deacetylase in somatic tissues and H3K4 trimethylation in germlines, there is scant evidence implicating epigenetic regulations in aging. The insulin/IGF-1 signaling (IIS) pathway is a major lifespan regulatory pathway. Here we show that progressive increases in gene expression and loss of H3K27me3 on IIS components are due, at least in part, to increased activity of the H3K27 demethylase UTX-1 during aging. RNAi of the utx-1 gene extended the mean lifespan of C. elegans by ~30%, dependent on DAF-16 activity and not additive in daf-2 mutants. The loss of utx-1 increased H3K27me3 on the Igf1r/daf-2 gene and decreased IIS activity leading to a more "naive" epigenetic state. Like stem cell reprogramming, our results suggest that reestablishing epigenetic marks lost during aging might help "reset" the developmental age of animal cells. Examination of H3K27me3 in young and old worms without or with Utx-1 RNAi.

2011-11-22 | E-GEOD-29896 | biostudies-arrayexpress

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression]

Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naM-CM-/ve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage. Samples include UTX+/Y (WT) and UTX-/Y (KO) cells from mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors). One sample is OSKM-induced Nanog-/- fibroblasts.

2012-05-29 | E-GEOD-35775 | biostudies-arrayexpress

Alternative mRNA splicing controls functions of the human H3K27 demethylase UTX/KDM6A

Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.

2024-01-28 | PXD041254 | Pride

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency

Project description:This SuperSeries is composed of the following subset Series: GSE35775: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression] GSE37821: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq] Refer to individual Series

2012-05-29 | E-GEOD-37822 | biostudies-arrayexpress

Mus musculus

Project description:UTX controls lineage-specific epigenetic program of iNKT cells

| PRJNA328452 | ENA

Mus musculus

Project description:UTX controls lineage-specific epigenetic program of iNKT cells

| PRJNA327821 | ENA

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq]

Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naïve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage.

2012-05-30 | GSE37821 | GEO

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