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Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism

ABSTRACT: Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism

PROVIDER: PRJNA525356 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8618190_1.fastq.gz	Fastqsanger.gz
	SRR8618190_2.fastq.gz	Fastqsanger.gz
	SRR8618191_1.fastq.gz	Fastqsanger.gz
	SRR8618191_2.fastq.gz	Fastqsanger.gz
	SRR8618192_1.fastq.gz	Fastqsanger.gz

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Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [I]

Project description:Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [I]

| PRJNA524108 | ENA

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [II]

Project description:Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [II]

| PRJNA525357 | ENA

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [III]

Project description:Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [III]

| PRJNA526044 | ENA

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [III]

Project description:T helper (Th) cells are CD4+ effector T cells that play an instrumental role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations, including autoimmune conditions such as ankylosing spondylitis. Here we identify KDM6A/KDM6B histone H3K27 demethylases by inhibitor and knockdown approaches as central regulators of human Th1, Th2 and Th17 subsets and establish a direct link between KDM6A/KDM6B in regulating Th17 cell metabolism. In mature Th17 cells demethylase inhibition leads to suppression of IL-17 cytokine levels and reduced proliferation through a pronounced ATF4 driven metabolic stress response in T cells derived from PBMC fractions of healthy donors and patients with ankylosing spondylitis. Metabolomic analyses reveal that Th17 T-cell differentiation is associated with an increase in glycolytic metabolism, pentosephosphate pathway activity and protein glycosylation intermediates. GSK-J4 treatment was shown to be overtly impactful on the cellular biochemistry of Th17 differentiated T-cells, with prominent effects on differentiation-related changes in glucose utilization, anabolic processes, and a remarkable change in amino acid and TCA cycle metabolism. During differentiation from naïve Th precursors to mature Th17 populations, demethylase inhibition with the prototypic inhibitor GSK-J4 leads to increases of repressive H3K27me3 chromatin marks, thereby down-regulating the required TH17 key transcription factor RORC and effectively suppressing metabolic reprogramming from a naïve T cell ground state to a differentiated subset. These data are consistent with an opposing effect of GSK-J4 on Th17 T-cell differentiation pathways directly related to proliferation and effector cytokine profiles.

2020-02-13 | GSE128008 | GEO

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [II]

2020-02-13 | GSE127766 | GEO

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism [I]

2020-02-13 | GSE126991 | GEO

Histone H3K27 demethylases regulate human Th17 cell maturation and effector functions by impacting on metabolism

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-02-13 | GSE127767 | GEO

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism.

Project description:T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.

| S-EPMC7084125 | biostudies-literature

RNA-seq analysis of peripheral nerve with conditional knockout of H3K27 demethylases.

Project description:The goal of the experiment was to determine the role of H3 emethylases in the nerve injury response in peripheral nerve. A Schwann cell specific knockout of the H3K27 demethylases (Jmjd3 and Utx) was generated to compare with wild type mice in sham and injured mice at 1d and 7d timepoints after nerve injury.

2021-06-25 | GSE178872 | GEO

RNA-seq analysis of peripheral nerve with conditional knockout of H3K27 demethylases.

Project description:RNA-seq analysis of peripheral nerve with conditional knockout of H3K27 demethylases.

| PRJNA741269 | ENA