Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
The EMBO Journal (Impact Factor: 10.43). 03/2013; 32(8). DOI: 10.1038/emboj.2013.54
Histone chaperones affect chromatin structure and gene expression through interaction with histones and RNA polymerase II (PolII). Here, we report that the histone chaperone Spt6 counteracts H3K27me3, an epigenetic mark deposited by the Polycomb Repressive Complex 2 (PRC2) and associated with transcriptional repression. By regulating proper engagement and function of the H3K27 demethylase KDM6A (UTX), Spt6 effectively promotes H3K27 demethylation, muscle gene expression, and cell differentiation. ChIP-Seq experiments reveal an extensive genome-wide overlap of Spt6, PolII, and KDM6A at transcribed regions that are devoid of H3K27me3. Mammalian cells and zebrafish embryos with reduced Spt6 display increased H3K27me3 and diminished expression of the master regulator MyoD, resulting in myogenic differentiation defects. As a confirmation for an antagonistic relationship between Spt6 and H3K27me3, inhibition of PRC2 permits MyoD re-expression in myogenic cells with reduced Spt6. Our data indicate that, through cooperation with PolII and KDM6A, Spt6 orchestrates removal of H3K27me3, thus controlling developmental gene expression and cell differentiation.
". On the other hand, KDM6A has been directly linked to transcriptional elongation through its interaction with RNA Polymerase II via Spt6 . Furthermore, PRC2 specifically resides at genes encoding developmental regulators (e.g., HOX genes) and its absence leads to embryonic stem cell differentiation defects and a delay in the loss of pluripotency . "
[Show abstract][Hide abstract] ABSTRACT: In recent years, there has been a boom in the amount of genome-wide sequencing data that has uncovered important and unappreciated links between certain genes, families of genes and enzymatic processes and diseases such as cancer. Such studies have highlighted the impact that chromatin modifying enzymes could have in cancer and other genetic diseases. In this review, we summarize characterized mutations and single nucleotide polymorphisms (SNPs) in histone lysine methyltransferases (KMTs), histone lysine demethylases (KDMs) and histones. We primarily focus on variants with strong disease correlations and discuss how they could impact histone lysine methylation dynamics and gene regulation. This article is part of a Special Issue entitled: Methylation Multifaceted Modification - looking at transcription and beyond.
"Interestingly, JMJD3 has also been shown to interact with the H3K36 methyltransferase SetD2 (Chen et al, 2012), which mediates H3K36-trimethylation in the body of transcribed genes. While the association of Spt6 and UTX with SetD2 was not examined in myoblasts, loss of Spt6 leads to a decrease in H3K36me3 accumulation within muscle genes (Wang et al, 2013). This would suggest that an ability to associate with additional components of the transcriptional elongation machinery is likely conserved between UTX and JMJD3. "
[Show abstract][Hide abstract] ABSTRACT: Spt6 is a highly conserved histone chaperone that interacts directly with both RNA polymerase II and histones to regulate
gene expression. To gain a comprehensive understanding of the roles of Spt6, we performed genome-wide analyses of transcription,
chromatin structure, and histone modifications in a Schizosaccharomyces pombe spt6 mutant. Our results demonstrate dramatic changes to transcription and chromatin structure in the mutant, including elevated
antisense transcripts at >70% of all genes and general loss of the +1 nucleosome. Furthermore, Spt6 is required for marks
associated with active transcription, including trimethylation of histone H3 on lysine 4, previously observed in humans but
not Saccharomyces cerevisiae, and lysine 36. Taken together, our results indicate that Spt6 is critical for the accuracy of transcription and the integrity
of chromatin, likely via its direct interactions with RNA polymerase II and histones.
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