Depletion of H3K36me2 recapitulates epigenomic and phenotypic changes induced by the H3.3K36M oncohistone mutation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE160266 | GEO | 2021/02/23
REPOSITORIES: GEO
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Project description:Hotspot histone H3 mutations have emerged as drivers of oncogenesis in cancers of multiple lineages. Specifically, H3 lysine 36 to methionine (H3K36M) mutations are recurrently identified in chondroblastomas, undifferentiated sarcomas, and head and neck cancers. While the mutation reduces global levels of both H3K36 dimethylation (H3K36me2) and trimethylation (H3K36me3) by dominantly inhibiting their respective specific methyltransferases, the relative contribution of these methylation states to the chromatin and phenotypic changes associated with H3K36M remains unclear. Here, we specifically deplete H3K36me2 or H3K36me3 in mesenchymal cells, using CRISPR-Cas9 to separately knock out the corresponding methyltransferases NSD1/2 or SETD2. By profiling and comparing the epigenomic and transcriptomic landscapes of these cells with cells expressing the H3.3K36M oncohistone, we find that the loss of H3K36me2 could largely recapitulate H3.3K36M's effect on redistribution of H3K27 trimethylation (H3K27me3) and gene expression. Consistently, knockout of Nsd1/2, but not Setd2, phenocopies the differentiation blockade and hypersensitivity to the DNA-hypomethylating agent induced by H3K36M. Together, our results support a functional divergence between H3K36me2 and H3K36me3 and their nonredundant roles in H3K36M-driven oncogenesis.
| S-EPMC7936350 | biostudies-literature
Project description:Depletion of H3K36me2 recapitulates epigenomic and phenotypic changes induced by the H3.3K36M oncohistone mutation
| PRJNA672721 | ENA
Project description:The lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, displacement of methylation at lysine 27 of histone H3 (H3K27me2/3), and thus promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.
2021-07-21 | GSE174006 | GEO
Project description:Over 90% of chondroblastomas contain a heterozygous mutation replacing lysine 36 with methionine (K36M) in the histone H3 variant H3.3. The role of the H3.3K36M mutation in tumorigenesis of this typically benign bone tumor with high recurrence rates is unknown. Here, we show that H3K36 di- and tri-methylation (me2 and me3) levels are reduced globally in chondroblastomas, as well as in chondrocytes stably expressing the H3.3K36M mutation because the H3.3M36 mutation protein inhibits the activity of lysine methyl transferases, MMSET and SetD2. Remarkably, at gene bodies, H3K36me2 increases and H3K36me3 decreases, which correlates with elevated and reduced expression of the underlying genes, respectively. Genes with altered H3K36me2/me3 and gene expression are associated with cancer pathways and chondrocyte differentiation. Chondrocytes harboring the H3.3K36M mutation exhibit cancer-associated cellular phenotypes and delayed chondrocyte differentiation associated with reduced Bmp2 and Runx2 expression. Exogenous Bmp2 partially rescued the delays in chondrocyte differentiation. Thus, H3.3K36M mutant proteins dominantly reprogram H3K36me2/me3 and chondrocyte gene expression, inhibiting terminal chondrocyte differentiation and contributing to tumorigenesis.
2016-10-06 | GSE75234 | GEO
Project description:We examined the genome-wide occupancy of H3K36me2/H3K36me3 in the transgenic plants HA-Ehd3/ehd3-1-1 and HA-Ehd3mu/ehd3-1-1.
2026-01-26 | GSE311864 | GEO
Project description:Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.
2022-07-07 | GSE183969 | GEO
Project description:Enzymes catalyzing CpG methylation in DNA, including DNMT1 and DNMT3A/B, are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting a critical role of DNA methylation during cell fate specification and maintenance. Recent studies suggest that histone post-translational modifications (PTMs) are involved in specifying patterns of DNMT localization and DNA methylation at promoters and actively transcribed gene bodies. However, mechanisms governing the establishment and maintenance of intergenic DNA methylation remain poorly understood. Germline mutations in DNMT3A lead to a childhood overgrowth syndrome that is phenotypically overlapping with Sotos syndrome caused by haploinsufficiency of NSD1, a histone methyltransferase catalyzing di-methylation on H3K36 (H3K36me2), pointing to a potential mechanistic link between the two disorders. Here we report that NSD1-mediated H3K36me2 is required for recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows binding and activity of DNMT3A are co-localized with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of NSD1 and its paralogue NSD2 in mouse and human cells redistributes DNMT3A to H3K36me3-marked gene bodies and reduces intergenic DNA methylation. NSD1 mutant tumors and Sotos patient samples are also associated with intergenic DNA hypomethylation. Consistently, PWWP-domain of DNMT3A shows dual recognition of H3K36me2/3 in vitro with a higher binding affinity towards H3K36me2, which is abrogated by overgrowth syndrome-derived missense mutations. Taken together, our study uncovers a trans-chromatin regulatory pathway that, when perturbed, promotes neoplastic and developmental overgrowth.
2019-08-30 | GSE118785 | GEO
Project description:Set2p, which mediates histone H3 Lysine 36 dimethylation (H3K36me2) in Saccharomyces cerevisiae, has been shown to associate with RNA polymerase II (RNAP II) at individual loci. Here, ChIP-chip experiments normalized to general nucleosome occupancy reveal that nucleosomes within open reading frames (ORFs) and downstream non-coding chromatin were highly dimethylated at H3K36, and that Set2p activity begins at a stereotypic distance from the initiation of transcription genome-wide. H3K36me2 is scarce in regions upstream of divergently transcribed genes, telomeres, silenced mating loci, and regions transcribed by RNA polymerase III, providing evidence that the enzymatic activity of Set2p is restricted to its association with RNAP II. The presence of H3K36me2 within ORFs correlated with the "on" or "off" state of transcription, but the degree of H3K36 dimethylation within ORFs did not correlate with transcription frequency. This provides evidence that H3K36me2 is established during the initial instances of gene transcription, with subsequent transcription having at most a maintenance role. Accordingly, newly activated genes acquire H3K36me2 in a manner that does not correlate with gene transcript levels. Finally, nucleosomes dimethylated at H3K36 appear to be refractory to loss from highly transcribed chromatin. Thus H3K36me2, which is highly conserved throughout eukaryotic evolution, provides a stable molecular mechanism for establishing chromatin context throughout the genome by distinguishing potential regulatory regions from transcribed chromatin. Keywords: ChIP-chip
2005-10-01 | GSE2991 | GEO
Project description:Monomethylation of histone H3 lysine 4 (H3K4me1) marks enhancers in mammals. However, the function of H3K4me1 in plants remains largely unclear. Here, we analyzed the genome-wide distribution of H3K4me1 in diverse species across evolution, revealing a distinctive H3K4me1 distribution pattern in land plants. To explore the function of H3K4me1 in plants, we identified an H3K4me1-specific reader protein, Early heading date 3 (Ehd3), and solved the structure of Ehd3 in complex with the H3K4me1 peptide, revealing a unique binding module differing from the previously reported PHD finger proteins. We further identified an Ehd3-binding protein, SET domain group 724 (SDG724), and the deletion of either Ehd3 or SDG724 caused similar defects in plant phenotype and changes in transcriptome and epigenome profiles. Both Ehd3 and SDG724 are enriched at chromatin regions marked by H3K4me1 but not H3K4me2 or H3K4me3. Ehd3 activates the H3K36 methyltransferase SDG724, and H3K36me2/me3 are colocalized with H3K4me1 in the genomes of land plants. Collectively, our results reveal that H3K4me1 directs the establishment of H3K36me2 and H3K36me3 in land plants.
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