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Spatial partitioning of NSD2 deposits H3K36me2 as an active histone mark to promote repetitive sequence expression [TT-Seq]

ABSTRACT: Histone H3 lysine 36 dimethylation (H3K36me2) plays a key role in transcriptional elongation and chromatin organization, yet how its deposition is spatially controlled across the genome remains unclear. Here, we identify TOP1 as a critical recruiter of the H3K36me2 methyltransferase NSD2 to gene bodies. Disruption of the TOP1–NSD2 interaction reduces H3K36me2 at gene bodies, impairs RNA Polymerase II release, and represses transcription. Remarkably, loss of this recruitment increases H3K36me2 at repetitive sequences, licensing their aberrant transcriptional activation. Subsequently, we identify MTA1 as a principal recruiter of NSD2 at these repetitive sequences through the recognition of consensus sequence GATC. Together, we demonstrate that TOP1 and MTA1 orchestrate NSD2 binding to direct its genomic distribution. Our study elucidates a complex recruitment mechanism that spatially partitions NSD2, thereby establishing the bifunctional role of H3K36me2 in regulating canonical gene expression and serving as an active mark for the transcriptional activation of repetitive sequences.

ORGANISM(S): Mus musculus

PROVIDER: GSE303597 | GEO | 2026/08/24

REPOSITORIES: GEO

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Spatial partitioning of NSD2 deposits H3K36me2 as an active histone mark to promote repetitive sequence expression [CUT&Tag]

Project description:Histone H3 lysine 36 dimethylation (H3K36me2) plays a key role in transcriptional elongation and chromatin organization, yet how its deposition is spatially controlled across the genome remains unclear. Here, we identify TOP1 as a critical recruiter of the H3K36me2 methyltransferase NSD2 to gene bodies. Disruption of the TOP1–NSD2 interaction reduces H3K36me2 at gene bodies, impairs RNA Polymerase II release, and represses transcription. Remarkably, loss of this recruitment increases H3K36me2 at repetitive sequences, licensing their aberrant transcriptional activation. Subsequently, we identify MTA1 as a principal recruiter of NSD2 at these repetitive sequences through the recognition of consensus sequence GATC. Together, we demonstrate that TOP1 and MTA1 orchestrate NSD2 binding to direct its genomic distribution. Our study elucidates a complex recruitment mechanism that spatially partitions NSD2, thereby establishing the bifunctional role of H3K36me2 in regulating canonical gene expression and serving as an active mark for the transcriptional activation of repetitive sequences.

2026-08-24 | GSE303600 | GEO

Spatial partitioning of NSD2 deposits H3K36me2 as an active histone mark to promote repetitive sequence expression [RNA-Seq]

2026-08-24 | GSE303602 | GEO

Spatial partitioning of NSD2 deposits H3K36me2 as an active histone mark to promote repetitive sequence expression [ChIP-Seq]

2026-08-24 | GSE303598 | GEO

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [ChIP]

Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. ChIP sequencing of H3K36me2 ChIP DNA from KMS11 and TKO2 cells using Illumina Solexa Genome Analyzer II single end sequencing protocol. The experiment contains two biological replicates of H3K36me2 ChIP DNA and input materials from KMS11 and TKO2 cells.

2011-11-29 | E-GEOD-29146 | biostudies-arrayexpress

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [RNAi]

Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 cells stably transduced with control vector in comparison to two independent shRNAs against NSD2. Each cell line is tested in duplicate.

2011-11-29 | E-GEOD-29147 | biostudies-arrayexpress

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [Transduction]

Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of p19ARF-/- mouse embryonic fibroblasts stably transduced with control vector or wild-type NSD2. Each cell line is tested in triplicate.

2011-11-29 | E-GEOD-29150 | biostudies-arrayexpress

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [TKO]

Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 and t(4;14) translocation knockout (TKO) cells. Each cell line is tested in triplicate.

2011-11-29 | E-GEOD-29148 | biostudies-arrayexpress

Antagonistic roles of histone 3 lysine methyltransferases dictate tumor immune surveillance

Project description:Histone H3 lysine 36 (H3K36) methyltransferases are frequently mutated in cancer, but their functional roles remain unclear. Using functional genomics approaches within KRAS-driven lung cancer models, we show that NSD2, SETD2, and EZH2 work in concert to regulate expression of endogenous retroviral elements, which act as a molecular rheostat controlling immune surveillance. Specifically, loss of H3K36me2 and H3K36me3 activity through H3K36M oncohistone expression or H3K36me2 alone through NSD2 inactivation leads to derepression of endogenous retroviral element transcripts that activate a dsRNA-mediated antiviral-like immune response that potently eradicates KRAS-driven tumor growth. Surprisingly, derepression of ERV sequences and subsequent immune reactions are completely dependent on SETD2, a tumor suppressor in KRAS-driven lung cancer that directly mediates H3K36me3 deposition. Mechanistically, inactivation of both NSD2 and SETD2 attenuates immune reactions by activating EZH2-dependent H3K27me3 and transcript repression at ERV sequences. These findings define an enzymatic triad of NSD2, SETD2, and EZH2 whose coordinated activities link chromatin regulation and tumor immune surveillance, revealing new epigenetic vulnerabilities in cancer.

2026-07-22 | PXD069619 | Pride

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [RNAi]

2011-11-29 | GSE29147 | GEO

Loss of NSD2 causes dysregulation of synaptic genes and altered H3K36 dimethylation in mice [ChIP-seq]

Project description:Epigenetic disruptions have been implicated in neurodevelopmental disorders. NSD2 is associated with developmental delay/ intellectual disability; however, its role in brain development and function remains unclear. We performed transcriptomic and epigenetic analyses using Nsd2 knockout mice to better understand the role of NSD2 in the brain. Transcriptomic analysis revealed that the loss of NSD2 caused dysregulation of genes related to synaptic transmission and formation. By analyzing changes in H3 lysine 36 dimethylation (H3K36me2), NSD2-mediated H3K36me2 mainly marked quiescent state regions and the redistribution of H3K36me2 occurred at transcribed genes and enhancers. By integrating transcriptomic and epigenetic data, we observed that H3K36me2 changes in a subset of dysregulated genes related to synaptic transmission and formation. These results suggest that NSD2 is involved in the regulation of genes important for neural function through H3K36me2. Our findings provide insights into the role of NSD2 and improve our understanding of epigenetic regulation in the brain.

2024-02-07 | GSE232561 | GEO

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