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SET1B facilitates activation of the hypoxia response through site-specific histone methylation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169041 | GEO | 2021/04/30

REPOSITORIES: GEO

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SET1B facilitates activation of the hypoxia response through site-specific histone methylation

Project description:Hypoxia-inducible transcription factors (HIFs) are fundamental to the cellular adaptation to low oxygen levels but how they interact with chromatin and efficiently activate their target genes is unclear. Using genome-wide mutagenesis in human cancer cells, we define genes required for HIF transcriptional activation, and identify a requirement for the Histone 3 lysine 4 (H3K4) methyltransferase SET1B. Loss of SET1B leads to a selective reduction in HIF transcriptional activity in hypoxia, with SET1B driving expression of genes involved in angiogenesis rather than glycolysis, resulting in impaired tumour establishment in SET1B deficient xenografts. Mechanistically, we show that SET1B is itself oxygen regulated, accumulates on chromatin in hypoxia, and is recruited to HIF target genes through HIF-1a. Accordingly, we show that the hypoxic induction of H3K4me3 at specific HIF targets is both HIF and SET1B dependent, and when impaired, decreases promotor acetylation and gene expression. Together, these findings reveal SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated.

2021-05-04 | GSE169087 | GEO

SET1B facilitates activation of the hypoxia response through site-specific histone methylation [ChIP-seq_1]

2021-04-30 | GSE159128 | GEO

SET1B facilitates activation of the hypoxia response through site-specific histone methylation [ChIP-seq_2]

2021-04-30 | GSE169040 | GEO

SET1B facilitates activation of the hypoxia response through site-specific histone methylation

Project description:SET1B facilitates activation of the hypoxia response through site-specific histone methylation

| PRJNA715190 | ENA

SET1B facilitates activation of the hypoxia response through site-specific histone methylation

Project description:SET1B facilitates activation of the hypoxia response through site-specific histone methylation

| PRJNA714950 | ENA

SET1B facilitates activation of the hypoxia response through site-specific histone methylation [ChIP-seq_1]

Project description:SET1B facilitates activation of the hypoxia response through site-specific histone methylation [ChIP-seq_1]

| PRJNA667729 | ENA

SET1B facilitates activation of the hypoxia response through site-specific histone methylation [ChIP-seq_2]

Project description:SET1B facilitates activation of the hypoxia response through site-specific histone methylation [ChIP-seq_2]

| PRJNA714954 | ENA

The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes.

Project description:Hypoxia-inducible transcription factors (HIFs) are fundamental to cellular adaptation to low oxygen levels, but it is unclear how they interact with chromatin and activate their target genes. Here, we use genome-wide mutagenesis to identify genes involved in HIF transcriptional activity, and define a requirement for the histone H3 lysine 4 (H3K4) methyltransferase SET1B. SET1B loss leads to a selective reduction in transcriptional activation of HIF target genes, resulting in impaired cell growth, angiogenesis and tumor establishment in SET1B-deficient xenografts. Mechanistically, we show that SET1B accumulates on chromatin in hypoxia, and is recruited to HIF target genes by the HIF complex. The selective induction of H3K4 trimethylation at HIF target loci is both HIF- and SET1B-dependent and, when impaired, correlates with decreased promoter acetylation and gene expression. Together, these findings show SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated.

| S-EPMC7611696 | biostudies-literature

Site-specific human histone H3 methylation stability: fast K4me3 turnover.

Project description:We employ stable-isotope labeling and quantitative mass spectrometry to track histone methylation stability. We show that H3 trimethyl K9 and K27 are slow to be established on new histones and slow to disappear from old histones, with half-lives of multiple cell divisions. By contrast, the transcription-associated marks K4me3 and K36me3 turn over far more rapidly, with half-lives of 6.8 h and 57 h, respectively. Inhibition of demethylases increases K9 and K36 methylation, with K9 showing the largest and most robust increase. We interpret different turnover rates in light of genome-wide localization data and transcription-dependent nucleosome rearrangements proximal to the transcription start site.

| S-EPMC4184988 | biostudies-literature

Inhibitor of CBP Histone Acetyltransferase Downregulates p53 Activation and Facilitates Methylation at Lysine 27 on Histone H3.

Project description:Tumor suppressor p53-directed apoptosis triggers loss of normal cells, which contributes to the side-effects from anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology emerging from anticancer therapies. Acetylation of p53 by the histone acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity and downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, the recruitment of p53 as well as RNA Polymerase II and levels of acetylation on histone H3 were diminished by NiCur. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of trimethylation at lysine 27. Finally, NiCur attenuates p53-directed apoptosis by inhibiting the Caspase 3 activity and cleavage of Poly (ADP-ribose) polymerase (PARP) in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.

| S-EPMC6222455 | biostudies-literature

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