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Methionine availability influences essential H3K36me3 dynamics during cell differentiation [ATAC-seq]

ABSTRACT: Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2, which senses methionine levels. Additionally, methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.

ORGANISM(S): Mus musculus

PROVIDER: GSE248197 | GEO | 2023/11/30

REPOSITORIES: GEO

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Methionine availability influences essential H3K36me3 dynamics during cell differentiation [ChIP-seq]

Project description:Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2, which senses methionine levels. Additionally, methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.

2023-11-30 | GSE248198 | GEO

Cryo-EM structure of SETD2/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations

Project description:Setd2 methylate the nucleosome to form H3K36me3. Here we utilized the Cryo-EM to elucidate the structure of SETD2/Set2 bound with nucleosomes. Through this structure analysis, we found that histone H1 may interfere the enzymatic activity of SETD2/Set2 by inhibiting their binding affinity.

2021-05-20 | GSE148235 | GEO

Gene expression analysis of murine renal tubular epithelial cells upon SETD2 knockout [RNAseq_RTE]

Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.

2021-11-15 | GSE146541 | GEO

Gene expression analysis of ccRCC cell line upon SETD2 rescue [RNAseq_JHRCC12]

2021-11-15 | GSE146540 | GEO

Genome binding/occupancy profiling of ccRCC cell line upon SETD2 rescue [ChIPseq_JHRCC12]

2021-11-15 | GSE146539 | GEO

Chromatin landscape analysis of murine renal tubular epithelial cells upon SETD2 knockout [ATACseq_RTE]

2021-11-15 | GSE146538 | GEO

Chromatin landscape analysis of ccRCC cell line upon SETD2 rescue [ATACseq_JHRCC12]

2021-11-15 | GSE146537 | GEO

Setd2-dependent H3K36me3 is required for Acrbp1 and protamine transcriptions and spermiogenesis in mice

Project description:Spermatogenesis is precisely cotrolled by complex gene expression programs and involves epigenetic reprogramming including histone modification and DNA methylation. Setd2 catalyzes the trimethylation of histone H3 Lys36 (H3K36me3) and plays key roles in embryonic stem cell differentiation and somatic cell development; however, its role in male germ cell development remains elusive. Here we demonstrate an essential role of Setd2 for spermiogenesis. We show that targeted knockout of Setd2 in germ cells causes aberrant spermiogenesis with acrosomal malformation before step 8 round spermatid stage, resulting in complete male infertile. Furthermore, we show a complete loss of H3K36me3 and a significant altered gene expression profile, including Acrbp1 and protamines, caused by Setd2 deficiency. Our findings reveal a previously underappreciated role of Setd2-dependent H3K36me3 for spermiogenesis and improved the understanding of epigenetic disorders underlying male infertility.

2018-04-28 | GSE108717 | GEO

setd2 knockout zebrafish is survivable and fertile: differential and developmental-stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals

Project description:Setd2 is the only enzyme that catalyzes histone H3 lysine 36 trimethylation (H3K36me3) on virtually all actively transcribed protein-coding genes, and this mechanism is evolutionarily conserved from yeast to human. Setd2 and H3K36me3 have been revealed to be involved in many important biochemical mechanisms, including DNA repair, alternative mRNA splicing and transcription elongation. However, physiological function of Setd2 in the context of zebrafish development remains elusive. Here we generated zebrafish setd2 mutant lines through disrupting the majority of the protein. And mRNA profiles of wild-type (WT), Setd2(+/-) and Setd2(-/-) zebrafish embryos at 36hpf were generated by deep sequencing, providing an opportunity to uncover molecular programs and functions of Setd2.

2020-05-27 | GSE151238 | GEO

Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice

Project description:Epigenetic regulation of gene expression through histone modifications like methylation of various lysine residues are essential for embryonic development. Here we removed SETD2, a methyltransferase for histone 3 lysine 36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and show it is required for proper area patterning (arealization) of the neocortex and the formation of thalamo-cortico-thalamic circuits by maintaining the expression of clustered protocadherin (Pcdh) genes in an H3K36me3 methyltransferase-dependent manner. Moreover, the Setd2 mutant mice exhibit defects in social interaction, motor endurance and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing SETD2 mutations.

2020-10-01 | GSE138153 | GEO

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