The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis

Wang, A Hongjun; Zare, Hossein; Mousavi, Kambiz; Wang, Chaochen; Moravec, Cara E.; Sirotkin, Howard I.; Ge, Kai; Gutierrez-Cruz, Gustavo; Sartorelli, Vittorio

doi:10.1038/emboj.2013.54

Cited by 66 publications

(76 citation statements)

References 44 publications

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“…The prevailing, albeit simplified, model of gene activation initiated by TF binding to enhancer sites consists of the following steps: (i) TF recruitment and possible nucleosome remodeling, (ii) histone acetyltransferase and mediator recruitment, (iii) BRD2/4 recruitment, and (iv) Pol II C-terminal domain (CTD) phosphorylation resulting in transcriptional elongation of target genes. Pol II elongation can be coupled to histone demethylation at H3K27 (19,20) and methylation at H3K4 (enhancers and promoters) and H3K36 (gene body) (20)(21)(22) (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

Iberg-Badeaux

Collombet

Beaugerie

et al. 2017

Molecular and Cellular Biology

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Short-term and long-term transcriptional memory is the phenomenon whereby the kinetics or magnitude of gene induction is enhanced following a prior induction period. Short-term memory persists within one cell generation or in postmitotic cells, while long-term memory can survive multiple rounds of cell division. We have developed a tissue culture model to study the epigenetic basis for longterm transcriptional memory (LTTM) and subsequently used this model to better understand the epigenetic mechanisms that enable heritable memory of temporary stimuli. We find that a pulse of transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣) induces LTTM on a subset of target genes that survives nine cell divisions. The chromatin landscape at genes that acquire LTTM is more repressed than at those genes that do not exhibit memory, akin to a latent state. We show through chromatin immunoprecipitation (ChIP) and chemical inhibitor studies that RNA polymerase II (Pol II) elongation is important for establishing memory in this model but that Pol II itself is not retained as part of the memory mechanism. More generally, our work reveals that a transcription factor involved in lineage specification can induce LTTM and that failure to rerepress chromatin is one epigenetic mechanism underlying transcriptional memory.

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Section: Resultsmentioning

confidence: 99%

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

Iberg-Badeaux

Collombet

Beaugerie

et al. 2017

Molecular and Cellular Biology

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“…In addition, spt6 mutations cause developmental defects in both Caenorhabditis elegans (35) and zebrafish (36). Studies in mammalian cells show that Spt6 is an important global regulator of transcription, including of genes implicated in cancer and viral infection, such as HIV and cytomegalovirus (CMV) (13,17,27,(37)(38)(39).Taken together, the documented effects of Spt6 on transcription and chromatin regulation are diverse and extensive. To more comprehensively understand the global roles of Spt6 in vivo, we have now systematically studied the genome-wide effects of Spt6 on transcription, chromatin structure, and three histone modifications in S. pombe.…”

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confidence: 99%

Spt6 Regulates Intragenic and Antisense Transcription, Nucleosome Positioning, and Histone Modifications Genome-Wide in Fission Yeast

DeGennaro

Alver

Marguerat³

et al. 2013

Molecular and Cellular Biology

143

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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. Studies over the last few years have revealed that transcription across eukaryotic genomes is much more widespread and complex than previously believed (1). Although it was once thought that transcription occurs primarily across protein-coding regions, genome-wide studies have now shown that transcription is also prevalent in intergenic regions and on antisense strands, in organisms ranging from yeast to humans (2, 3). Although roles for a small amount of this transcription have been established, for most, we have little understanding of its biological functions. Furthermore, while some factors have been shown to control the level of noncoding and antisense transcripts, many questions remain regarding the regulation of their synthesis and stability.One factor that plays a prominent role in the genome-wide control of transcription is Spt6. Originally identified in Saccharomyces cerevisiae (4, 5), Spt6 is conserved throughout eukaryotes and also has homology to the prokaryotic activator Tex (6). Spt6 interacts directly with several important factors, including RNA polymerase II (RNAPII) (7-11), histones (12, 13), and the transcription factor Iws1/Spn1 (7,14,15), suggesting that it is multifunctional. Recent studies in mammalian cells show that Spt6 also interacts directly with other chromatin related factors, including H3K27 demethylases (16, 17). Several gene-specific studies have demonstrated roles for Spt6 in transcription initiation (18)(19)(20), elongation (21, 22), and termination (23, 24). In addition, Spt6 is required for H3K36 methylation (25-28) and regulates nucleosome positioning and occupancy, particularly over highly expressed genes (12,19,29). Finally, Spt6 can assemble nucleosomes in vitro in an ATP-independent fashion (12). These results suggest that Spt6 acts as a histone chaperone by restoring nucleosomes in the wake of RNAPII transcription (30,31).In vivo, Spt6 is critical for normal growth and transcription. It is either essential or nearly essential for viability in all organisms tested, and viable spt6 mutations cause severe defects. In S. cerevisiae spt6 mutants,...

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“…Spt6 orchestrates H3K27 demethylation interacting with UTX and RNA Pol II at chromatin regions of muscle-specific genes, and it is required for appropriate muscle gene expression and myogenesis. 137 Following removal of H3K27me3, MyoD, acetyltransferases (HATs), and other transcription factors are recruited at musclespecific genes with consequent transcriptional activation and induction of skeletal muscle differentiation (Fig. 2).…”

Section: Role Of Ezh2 In Skeletal Myogenesismentioning

confidence: 99%

Roles of enhancer of zeste homolog 2: From skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis

Marchesi

Giordano

Bagella³

2014

Cell Cycle

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The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis

Cited by 66 publications

References 44 publications

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

Spt6 Regulates Intragenic and Antisense Transcription, Nucleosome Positioning, and Histone Modifications Genome-Wide in Fission Yeast

Roles of enhancer of zeste homolog 2: From skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis

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