Antagonistic roles of histone 3 lysine methyltransferases dictate tumor immune surveillance
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE334916 | GEO | 2026/07/21
REPOSITORIES: GEO
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Project description:Histone tails are post-translationally modified at multiple sites, including Lys36 on histone H3 (H3K36). The H3K36 methylation has been shown to associate with the transcription of active euchromatin, alternative splicing, DNA repair and recombination. However, the role of H3K36 methylation during cell differentiation is still obscure.Previous investigations found that a site specific Lys-to-Met mutation on histones can serve as an inhibitor of this site specific methyltransferases to repress global methylation on that lysine of histones. In this study we usedH3K36 Lys-to-Met mutant (H3K36M) as a tool to investigaterole of H3K36 methylation in our cell differentiation system. Expression of H3K36M repressed global H3K36 methylation but increased H3K27me3 as previously reported. On our cell differentiation system, H3K36M suppressed adipogenesis and myogenesis. Our pioneer RNA-seqstudy further showed that H3K36M repressed the expression of master regulator genes. Here, we did ChIP-seq of several histone modifications to further explore the changes on the epigenome by expression of H3K36M. Interestingly, on some important master regulator genes loci, the repressive marker H3K27me3 increased significantly, correlated with the repression on their expression. The H3K36M decreases global H3K36 di- and tri-methylation. To clarify which H3K36 methyltransferase is important for cell differentiation, we knocked down H3K36 di-methyltransferases Nsd1 and Nsd2, H3K36 tri-methyltransferase Setd2 separately. Nsd2 knockdown, but not Nsd1 or Setd2,can phenocopythe adipogenesis defect in H3K36M expressed cells.Comparing in RNA-seq results, Nsd2 knockdown cells showed similar gene expression profile with H3K36M expressed cells in adipogenesis. These suggest that Nsd2-mediated H3K36me2 plays an important role in adipogenesis.To study the role of H3K36 methylation in vivo, we generated an aP2 promoter driven H3K36M expressed transgenic mouse (Tg), to express H3K36M specifically in adipose tissue. The Tg mice showedsignificant dysfunction in both white and brown adipose tissues. Their fat tissues gene expression profile changed significantly. All of these indicate that H3K36 methylation is important for adipose tissue developmentin vivo.Together, our comprehensive studies provide novel insights into dynamics of H3K36 methylation and its important role in transcriptional regulation of cell differentiation and mouse fat tissue development.
2018-03-19 | GSE83793 | GEO
Project description:Mutations in histone 3 at or near lysine 36 (H3K36) have dominantly acting oncogenic effects in multiple tumor types by limiting H3K36-directed methyltransferases. Paradoxically, we find that expression of the H3K36M oncohistone unexpectedly inhibits tumor formation in KRAS-driven lung adenocarcinoma by inducing a potent immune-mediated tumor clearance. Mechanistically, oncohistone expression derepresses endogenous retroviral element transcription, results in the accumulation of double-stranded RNA (dsRNA), and activates an innate antiviral-like immune response that eradicates tumor growth. Surprisingly, while inactivation of the H3K36 di-methyltransferase NSD2 replicated all effects of oncohistone expression, inactivation of the H3K36 tri-methyltransferase SETD2 abolished element derepression and all associated downstream anti-cancer effects that are induced by oncohistone expression. These observations restructure our understanding of the roles of H3K36 methylation, the consequences of its deregulation in cancer, and shape our expectations for therapeutic interventions targeting H3K36 methyltransferases.
2026-07-21 | GSE335211 | GEO
Project description:H3K36 methylation is a key epigenetic mark with critical roles in development and disease, yet its genome-wide functions remain incompletely understood. Here, we systematically dissect the role of H3K36 methylation using a series of CRISPR-engineered mouse mesenchymal stem cell lines with progressive knockouts of the five H3K36 methyltransferases: NSD1, NSD2, NSD3, SETD2 and ASH1L—culminating in quintuple knockout (QuiKO) cells entirely lacking H3K36me2/3. We demonstrate that H3K36me2 enriched at active cis-regulatory elements predominantly influences enhancer activity and supports the expression of enhancer-dependent genes. Within gene bodies, loss of H3K36me2/3 permits invasion by the repressive H3K27me2/3 modifications, thereby disrupting transcriptional fidelity. Unexpectedly, we uncover a previously undescribed relationship between H3K36me and H3K9me3: upon H3K36me2 depletion, SUV39H1-mediated H3K9me3 redistributes from large constitutive heterochromatic domains into euchromatin, leading to widespread epigenome restructuring and transcriptional changes. This redistribution is accompanied by a collapse of 3D genome organization, including weakened compartment boundaries and a profound loss of long-range interactions. Finally, we validate key findings in two human HNSCC cell lines overexpressing the H3K36M oncohistone, highlighting the conserved role of H3K36 methylation in maintaining epigenome integrity across species and cell types, and providing further mechanistic insights into the downstream consequences of this oncogenic mutation. Together, these data reveal that H3K36me is essential not only for local gene regulation but also for safeguarding the higher-order structure and functional balance of the genome.
2025-10-23 | GSE274362 | GEO
Project description:H3K36 methylation is a key epigenetic mark with critical roles in development and disease, yet its genome-wide functions remain incompletely understood. Here, we systematically dissect the role of H3K36 methylation using a series of CRISPR-engineered mouse mesenchymal stem cell lines with progressive knockouts of the five H3K36 methyltransferases: NSD1, NSD2, NSD3, SETD2 and ASH1L—culminating in quintuple knockout (QuiKO) cells entirely lacking H3K36me2/3. We demonstrate that H3K36me2 enriched at active cis-regulatory elements predominantly influences enhancer activity and supports the expression of enhancer-dependent genes. Within gene bodies, loss of H3K36me2/3 permits invasion by the repressive H3K27me2/3 modifications, thereby disrupting transcriptional fidelity. Unexpectedly, we uncover a previously undescribed relationship between H3K36me and H3K9me3: upon H3K36me2 depletion, SUV39H1-mediated H3K9me3 redistributes from large constitutive heterochromatic domains into euchromatin, leading to widespread epigenome restructuring and transcriptional changes. This redistribution is accompanied by a collapse of 3D genome organization, including weakened compartment boundaries and a profound loss of long-range interactions. Finally, we validate key findings in two human HNSCC cell lines overexpressing the H3K36M oncohistone, highlighting the conserved role of H3K36 methylation in maintaining epigenome integrity across species and cell types, and providing further mechanistic insights into the downstream consequences of this oncogenic mutation. Together, these data reveal that H3K36me is essential not only for local gene regulation but also for safeguarding the higher-order structure and functional balance of the genome.
2025-10-23 | GSE274364 | GEO
Project description:H3K36 methylation is a key epigenetic mark with critical roles in development and disease, yet its genome-wide functions remain incompletely understood. Here, we systematically dissect the role of H3K36 methylation using a series of CRISPR-engineered mouse mesenchymal stem cell lines with progressive knockouts of the five H3K36 methyltransferases: NSD1, NSD2, NSD3, SETD2 and ASH1L—culminating in quintuple knockout (QuiKO) cells entirely lacking H3K36me2/3. We demonstrate that H3K36me2 enriched at active cis-regulatory elements predominantly influences enhancer activity and supports the expression of enhancer-dependent genes. Within gene bodies, loss of H3K36me2/3 permits invasion by the repressive H3K27me2/3 modifications, thereby disrupting transcriptional fidelity. Unexpectedly, we uncover a previously undescribed relationship between H3K36me and H3K9me3: upon H3K36me2 depletion, SUV39H1-mediated H3K9me3 redistributes from large constitutive heterochromatic domains into euchromatin, leading to widespread epigenome restructuring and transcriptional changes. This redistribution is accompanied by a collapse of 3D genome organization, including weakened compartment boundaries and a profound loss of long-range interactions. Finally, we validate key findings in two human HNSCC cell lines overexpressing the H3K36M oncohistone, highlighting the conserved role of H3K36 methylation in maintaining epigenome integrity across species and cell types, and providing further mechanistic insights into the downstream consequences of this oncogenic mutation. Together, these data reveal that H3K36me is essential not only for local gene regulation but also for safeguarding the higher-order structure and functional balance of the genome.
2025-10-23 | GSE274361 | GEO
Project description:H3K36 methylation is a key epigenetic mark with critical roles in development and disease, yet its genome-wide functions remain incompletely understood. Here, we systematically dissect the role of H3K36 methylation using a series of CRISPR-engineered mouse mesenchymal stem cell lines with progressive knockouts of the five H3K36 methyltransferases: NSD1, NSD2, NSD3, SETD2 and ASH1L—culminating in quintuple knockout (QuiKO) cells entirely lacking H3K36me2/3. We demonstrate that H3K36me2 enriched at active cis-regulatory elements predominantly influences enhancer activity and supports the expression of enhancer-dependent genes. Within gene bodies, loss of H3K36me2/3 permits invasion by the repressive H3K27me2/3 modifications, thereby disrupting transcriptional fidelity. Unexpectedly, we uncover a previously undescribed relationship between H3K36me and H3K9me3: upon H3K36me2 depletion, SUV39H1-mediated H3K9me3 redistributes from large constitutive heterochromatic domains into euchromatin, leading to widespread epigenome restructuring and transcriptional changes. This redistribution is accompanied by a collapse of 3D genome organization, including weakened compartment boundaries and a profound loss of long-range interactions. Finally, we validate key findings in two human HNSCC cell lines overexpressing the H3K36M oncohistone, highlighting the conserved role of H3K36 methylation in maintaining epigenome integrity across species and cell types, and providing further mechanistic insights into the downstream consequences of this oncogenic mutation. Together, these data reveal that H3K36me is essential not only for local gene regulation but also for safeguarding the higher-order structure and functional balance of the genome.
2025-10-23 | GSE274363 | GEO
Project description:H3K36 methylation is a key epigenetic mark with critical roles in development and disease, yet its genome-wide functions remain incompletely understood. Here, we systematically dissect the role of H3K36 methylation using a series of CRISPR-engineered mouse mesenchymal stem cell lines with progressive knockouts of the five H3K36 methyltransferases: NSD1, NSD2, NSD3, SETD2 and ASH1L—culminating in quintuple knockout (QuiKO) cells entirely lacking H3K36me2/3. We demonstrate that H3K36me2 enriched at active cis-regulatory elements predominantly influences enhancer activity and supports the expression of enhancer-dependent genes. Within gene bodies, loss of H3K36me2/3 permits invasion by the repressive H3K27me2/3 modifications, thereby disrupting transcriptional fidelity. Unexpectedly, we uncover a previously undescribed relationship between H3K36me and H3K9me3: upon H3K36me2 depletion, SUV39H1-mediated H3K9me3 redistributes from large constitutive heterochromatic domains into euchromatin, leading to widespread epigenome restructuring and transcriptional changes. This redistribution is accompanied by a collapse of 3D genome organization, including weakened compartment boundaries and a profound loss of long-range interactions. Finally, we validate key findings in two human HNSCC cell lines overexpressing the H3K36M oncohistone, highlighting the conserved role of H3K36 methylation in maintaining epigenome integrity across species and cell types, and providing further mechanistic insights into the downstream consequences of this oncogenic mutation. Together, these data reveal that H3K36me is essential not only for local gene regulation but also for safeguarding the higher-order structure and functional balance of the genome.
2025-10-23 | GSE274366 | GEO
Project description:Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its demonstrated importance in development, disease, and cancer, the molecular agents responsible for the deposition of H3K36me are not yet well understood. Here, we use a mouse mesenchymal stem cell model to comprehensively perturb the components of the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and that it is predominantly deposited at intergenic regions by NSD1, and in part by NSD2. In contrast, H3K36me1/3 are most abundant within exons and have a positive correlation with gene expression. We further demonstrate that while SETD2 is responsible for depositing most H3K36me3, it also deposits a modest amount of H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting that other H3K36 methyltransferases may prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the genome-wide distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits broad H3K36me2 peaks centered on active promoter and enhancer regions. Meanwhile, the activity of ASH1L is focused primarily on the promoters of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor for ASH1L to these regions. Overall, our study provides new insights into the regulation of H3K36me by the H3K36 methyltransferase family and helps to consolidate the wealth of previous observations in the context of a structured analysis.
2023-10-05 | MSV000093049 | MassIVE
Project description:Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development, disease, and cancer, how the molecular agents collectively shape the genome-wide deposition of H3K36me is unclear. Here, we use mouse mesenchymal stem cells to comprehensively perturb the components of the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and that it is predominantly deposited at intergenic regions by NSD1, and in part by NSD2. In contrast, H3K36me1/3 are most abundant within exons and are positively correlated with gene expression. We demonstrate that while SETD2 is responsible for depositing most H3K36me3, it also deposits H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting that other H3K36 methyltransferases may prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits H3K36me2 peaks centered on active promoter and enhancer regions. Meanwhile, the activity of ASH1L is restricted to regulatory elements of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor. Overall, our study provides new insights into the regulation of H3K36me and helps to consolidate the wealth of previous observations in the context of structured analyses.
2024-09-25 | GSE243566 | GEO
Project description:H3K36 methylation is emerging as a key epigenetic modification with strong involvement in genetic disease and cancer. The mechanisms through which H3K36me impacts the epigenome and asserts its functional consequences are far from understood. Here, we use mouse mesenchymal stem cell lines with successive knockouts of the H3K36 methyltransferases: NSD1, NSD2, SETD2, NSD3, and ASH1L, which result in progressive depletion of H3K36me and its complete absence in the quintuple KO cells, to finely dissect the role of H3K36me2 in shaping the epigenome and transcriptome. We show that H3K36me2, which targets active enhancers, is important for maintaining enhancer activity, and its depletion results in downregulation of enhancer-dependent genes. We demonstrate the roles of H3K36me2/3 in preventing the invasion of gene bodies by the silencing H3K27me modifications. Finally, we observe a previously undescribed relationship between H3K36me and H3K9me3: Following the depletion of H3K36me2, H3K9me3 is redistributed away from large heterochromatic domains and towards euchromatin. This results in a drastic decompartmentalization of the genome, weakening the boundaries between active and inactive compartments, and a catastrophic loss of long-range inter-compartment interactions. By studying cells totally devoid of H3K36 methyltransferase activity, we uncover a broad range of crucial functions of H3K36me in maintaining epigenome integrity.
2025-10-23 | GSE274365 | GEO