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Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

ABSTRACT: Although, IDH1 has been recognized to play critical roles in the regulation of dynamic chromatin states, the mechanism remained largely unknown. Here, using the human erythropoiesis system, we presented an innovative perspective of metabolism independent role of nuclear IDH1. We discovered that IDH1 acted as a nuclear located chromatin-binding protein. Knockdown of IDH1 induced chromatin reorganization and subsequently aroused aberrant biological events germination on erythroid precursors in a metabolism independent manner. IDH1 knockdown induced genome-wide coordinate changes in the distribution and intensity of multiple histone marks, among which H3K79me3 was identified to be the decisive factor in chromatin state reprogramming. Integrating ChIP-seq, ATAC-seq and RNA-seq recognized SIRT1 to be the key gene affected by IDH1 deficiency. Taken together, these findings provided a novel insight for further clarifying the fundamental biological function of IDH1 which had substantial implications for an in-depth understanding of the pathogenesis of diseases with IDH1 dysfunction and accordingly the development of therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222401 | GEO | 2025/01/01

REPOSITORIES: GEO

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Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

Project description:Although, IDH1 has been recognized to play critical roles in the regulation of dynamic chromatin states, the mechanism remained largely unknown. Here, using the human erythropoiesis system, we presented an innovative perspective of metabolism independent role of nuclear IDH1. We discovered that IDH1 acted as a nuclear located chromatin-binding protein. Knockdown of IDH1 induced chromatin reorganization and subsequently aroused aberrant biological events germination on erythroid precursors in a metabolism independent manner. IDH1 knockdown induced genome-wide coordinate changes in the distribution and intensity of multiple histone marks, among which H3K79me3 was identified to be the decisive factor in chromatin state reprogramming. Integrating ChIP-seq, ATAC-seq and RNA-seq recognized SIRT1 to be the key gene affected by IDH1 deficiency. Taken together, these findings provided a novel insight for further clarifying the fundamental biological function of IDH1 which had substantial implications for an in-depth understanding of the pathogenesis of diseases with IDH1 dysfunction and accordingly the development of therapeutic strategies.

2025-01-01 | GSE222296 | GEO

Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming [RNA-seq]

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Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

Project description:Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

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Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

Project description:Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

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Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming [RNA-seq]

Project description:Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming [RNA-seq]

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Epigenetic changes in human DIPG cells with histone H3K27M mutations [ATAC-seq]

Project description:We assessed changes in chromatin accessibility in H3.3K27M DIPG cell lines on knockdown of metabolic enzymes including HK2, GDH and IDH1

2020-06-24 | GSE135418 | GEO

Valproic acid targets IDH1 mutants through alteration of lipid metabolism [2022]

Project description:Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-epilepticseizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no change inenhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas.

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Valproic acid targets IDH1 mutants through alteration of lipid metabolism [2020]

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AF9 Links Histone Acetylation to DOT1L-Mediated H3K79 Methylation

Project description:The recognition of modified histones by “reader” proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the great variety of readers for histone methylation, few protein modules that recognize histone acetylation are known. Here we show that the evolutionarily conserved YEATS domains constitute a novel family of acetyllysine readers. The human AF9 YEATS domain binds strongly to histone H3K9 acetylation and, to a lesser extent, H3K27 and H3K18 acetylation. Crystal structural studies revealed that AF9 YEATS adopts an eight-stranded immunoglobin fold and utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout, representing a novel recognition mechanism that is distinct from that of known acetyllysine readers. Histone acetylation recognition by AF9 is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L. Together, our studies identify the YEATS domain as a novel acetyllysine-binding module, thereby establishing the first direct link between histone acetylation and DOTL1-mediated H3K79 methylation in transcription control. ChIP-seq analysis of AF9, H3K79me3, H3K9ac in Hela cells and H3K79me3 in Hela AF9 knockdown and Hela Dot1L knockdown cells.

2014-12-11 | E-GEOD-60366 | biostudies-arrayexpress

SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

Project description:The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact action mechanism of H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM36 taining Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a novel histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

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