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Histone H3K36M mutation impairs mesenchymal differentiation and drives sarcoma development [ChIP-Seq]

ABSTRACT: The goal of this study is to understand the genome-wide alterations in chromatin landscapy induced by a histone mutation (H3.3 K36M) derived from chondroblastomas

ORGANISM(S): Mus musculus

PROVIDER: GSE63193 | GEO | 2016/09/23

SECONDARY ACCESSION(S): PRJNA266971

REPOSITORIES: GEO

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Histone H3K36M mutation impairs mesenchymal differentiation and drives sarcoma development [RNA-Seq]

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The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas

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.

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Histone H3K36M mutation impairs mesenchymal differentiation and drives sarcoma development

Project description:This SuperSeries is composed of the SubSeries listed below.

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Histone H3K36M mutation impairs mesenchymal differentiation and drives sarcoma development [RNA_H33_K36M_HMT]

Project description:The goal of this study is to understand the alterations in transcriptome induced by histone H3K36M mutations

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Histone H3K36M mutation impairs mesenchymal differentiation and drives sarcoma development

Project description:Histone H3K36M mutation impairs mesenchymal differentiation and drives sarcoma development

| PRJNA266967 | ENA