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The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression.

ABSTRACT: Epigenetics, especially histone marks, functions beyond the DNA sequences to regulate gene expression. Depletion of NSD1, which catalyzes H3K36me2, leads to both up- and down-regulation of gene expression, indicating NSD1 is associated with both active and repressed gene expression. It's known that NSD1 regulates the deposition and expansion of H3K27me3, a repressive mark for gene expression, to keep active gene transcription. However, how NSD1 functions to repress gene expression is largely unknown. Here, we find that, when NSD1 is knocked out in mouse embryonic stem cells (mESCs), H3K27ac increases correlatively with the decrease of H3K36me2 at active enhancers, which is associated with mesoderm differentiation genes, leading to elevated gene expression. Mechanistically, NSD1 recruits HDAC1, the deacetylase of H3K27ac, to chromatin. Moreover, HDAC1 knockout (KO) recapitulates the increase of H3K27ac at active enhancers as the NSD1 depletion. Together, we propose that NSD1 deposits H3K36me2 and recruits HDAC1 at active enhancers to serve as a 'safeguard', preventing further activation of active enhancer-associated genes.

SUBMITTER: Fang Y

PROVIDER: S-EPMC8216457 | biostudies-literature |

REPOSITORIES: biostudies-literature

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NSD1-mediated HDAC1 recruitment reduces H3K27ac at active enhancers to safeguard associated gene expression

Project description:Epigenetics, especially histone marks, functions beyond the DNA sequences to regulate gene expression. Depletion of NSD1, which catalyzes H3K36me2, led to both up- and down-regulation of gene expression, indicating NSD1 is associated with both active and repressed gene expression. It’s known that NSD1 regulates the deposition and expansion of H3K27me3, a repressive mark for gene expression, to keep active gene transcription. However, how NSD1 functions to repress gene expression is largely unknown. Here, we found that, when NSD1 was knocked out in mouse embryonic stem cells (mESCs), H3K27ac increased correlatively with the decrease of H3K36me2 at active enhancers, which is associated with mesoderm differentiation genes, leading to elevated gene expression. Mechanistically, NSD1 recruits HDAC1, the deacetylase of H3K27ac, to chromatin. Moreover, HDAC1 knockout (KO) recapitulates the increase of H3K27ac at active enhancers as the NSD1 depletion. Together, we propose that NSD1 deposits H3K36me2 and recruits HDAC1 at active enhancers to serve as a ‘safeguard’, preventing further activation of active enhancer-associated genes.

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Project description:NSD1-mediated HDAC1 recruitment reduces H3K27ac at active enhancers to safeguard associated gene expression

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Project description:Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. While enhancer elements are known to be associated with certain histone modifications, and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements, thus providing clues to current cell state and further developmental potential. Gene expression profiling was performed in mouse ES, NPC, liver, and pro-B

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Lysine Methyltransferase NSD1 and Cancers: Any Role in Melanoma?

Project description:Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers.

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