H3.3 actively marks enhancers and primes gene transcription via opening higher-ordered chromatin

Chen, Ping; Zhao, Ji‐Cheng; Wang, Yan; Wang, Min; Long, Haizhen; Liang, Dan; Huang, Li; Wen, Zengqi; Li, Wei; Li, Xia; Feng, Hongli; Zhao, Hong; Zhu, Ping; Li, Ming; Wang, Qian-fei; Li, Guohong

doi:10.1101/gad.222174.113

Cited by 207 publications

(231 citation statements)

References 49 publications

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“…H3.3 normally is enriched in active genes and in regulatory regions (35). In fact, H3.3-containing regions display a looser and more open chromatin structure (35,36). Consistent with the partial reduction in the level of histones and the increased level of the A B open-chromatin-specific H3.3, we observed that chromatin was more accessible to MNase I in SLBP-silenced cells (Fig.…”

Section: Discussionsupporting

confidence: 72%

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Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Jimeno-González

Payán-Bravo

Muñoz-Cabello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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RNA polymerase II (RNAPII) transcription elongation is a highly regulated process that greatly influences mRNA levels as well as pre-mRNA splicing. Despite many studies in vitro, how chromatin modulates RNAPII elongation in vivo is still unclear. Here, we show that a decrease in the level of available canonical histones leads to more accessible chromatin with decreased levels of canonical histones and variants H2A.X and H2A.Z and increased levels of H3.3. With this altered chromatin structure, the RNAPII elongation rate increases, and the kinetics of pre-mRNA splicing is delayed with respect to RNAPII elongation. Consistent with the kinetic model of cotranscriptional splicing, the rapid RNAPII elongation induced by histone depletion promotes the skipping of variable exons in the CD44 gene. Indeed, a slowly elongating mutant of RNAPII was able to rescue this defect, indicating that the defective splicing induced by histone depletion is a direct consequence of the increased elongation rate. In addition, genome-wide analysis evidenced that histone reduction promotes widespread alterations in pre-mRNA processing, including intron retention and changes in alternative splicing. Our data demonstrate that premRNA splicing may be regulated by chromatin structure through the modulation of the RNAPII elongation rate. T he transcription process comprises several steps, including preinitiation complex formation, promoter escape, elongation, and termination (1). Recent reports indicate that elongation rates of RNA polymerase II (RNAPII) in mammals range from 0.5 to 4 kb/min, but which factors are responsible for these differences is still unclear (2-4). One obvious candidate for affecting transcription elongation is chromatin structure. The building block of chromatin is the nucleosome comprising 147 bp of DNA around a histone octamer formed by two H2A-H2B dimers and one H3-H4 tetramer. In vitro experiments have demonstrated that nucleosomes are a barrier for RNAPII transcription elongation (5, 6). We have reported that a nucleosome positioned in the body of a transcription unit impairs RNAPII progression in vivo (7). Furthermore, Weber et al. (8) have shown recently that RNAPII stalls in vivo at the entry site of essentially every transcribed nucleosome in Drosophila. Despite this evidence, it is still unclear whether changes in chromatin structure in different regions of a gene or between different genes can regulate the rate of transcription elongation.Transcription and splicing are coupled processes (9, 10). Splicing occurs cotranscriptionally, and multiple lines of evidence indicate that transcription elongation and splicing influence each other. On one hand, it has been suggested that splicing factors are recruited to the template by the transcription machinery (11, 12). On the other hand, the rate of RNAPII elongation influences splicing. The kinetic model proposes that a slow elongation rate facilitates weak splice-site recognition, promoting the inclusion of alternative exons (13, 14). However, recent studies have ex...

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Section: Discussionsupporting

confidence: 72%

“…However, the levels of the histone variant H3.3 increased strongly in SLBP-silenced cells. H3.3 normally is enriched in active genes and in regulatory regions (35). In fact, H3.3-containing regions display a looser and more open chromatin structure (35,36).…”

Section: Discussionmentioning

confidence: 99%

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Jimeno-González

Payán-Bravo

Muñoz-Cabello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Second, while the majority of eukaryotes express distinct histone H3 variants for replication-coupled (RC) (designated histone H3.1 and H3.2 in humans) and replicationindependent (RI) (designated histone H3.3 in humans) histone deposition, S. cerevisiae has retained a histone H3.3-like variant for both pathways. The amino acid differences between RC-and RI-specific H3 variants are proposed to restrict the histones to their requisite deposition pathways (Szenker et al 2011), but these variants also directly alter chromatin structure in vitro (Thakar et al 2009;Chen et al 2013). This together with the previously established link between H3.3 deposition and active transcription in metazoans (Waterborg 1990;Johnson et al 2004;McKittrick et al 2004;Chow et al 2005;Mito et al 2005) has led to speculation that yeasts have retained H3.3 due to its ability to promote an open chromatin conformation.…”

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confidence: 99%

Divergent Residues Within Histone H3 Dictate a Unique Chromatin Structure in Saccharomyces cerevisiae

et al. 2015

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Histones are among the most conserved proteins known, but organismal differences do exist. In this study, we examined the contribution that divergent amino acids within histone H3 make to cell growth and chromatin structure in Saccharomyces cerevisiae. We show that, while amino acids that define histone H3.3 are dispensable for yeast growth, substitution of residues within the histone H3 a3 helix with human counterparts results in a severe growth defect. Mutations within this domain also result in altered nucleosome positioning, both in vivo and in vitro, which is accompanied by increased preference for nucleosome-favoring sequences. These results suggest that divergent amino acids within the histone H3 a3 helix play organismal roles in defining chromatin structure. KEYWORDS histone; H3; S. cerevisiae; nucleosome positioning I N eukaryotes, DNA is packaged into a nucleoprotein structure known as chromatin, which consists of DNA, histones, and nonhistone proteins. The basic unit of chromatin is the nucleosome core particle, which is made up of an octamer of the four core histones, H2A, H2B, H3, and H4, wrapped with 147 bp of DNA (Luger et al. 1997;Kornberg and Lorch 1999). Although nucleosomes will form on most sequences in vitro, they are not randomly positioned in vivo. Genomewide mapping studies have shown that gene promoters and other regulatory regions tend to be nucleosome depleted and two general mechanisms have been proposed to explain this (Hughes and Rando 2014). First, certain DNA sequences, such as AT-rich regions, are refractory to nucleosome formation. Second, trans-acting factors, such as transcriptional activators, RNA polymerases, and ATP-dependent chromatin remodelers can either evict or reposition nucleosomes. Nucleosomes immediately adjacent to nucleosome-depleted regions (NDRs) are generally well positioned, but nucleosome position shows more cell-to-cell variability with increasing distance from NDRs (Yuan et al. 2005;Mavrich et al. 2008). This has led to proposal of the statistical positioning model, which suggests that strongly positioned nucleosomes create barriers against which other nucleosomes are packed into positioned and phased arrays (Kornberg and Stryer 1988;Zhang et al. 2011).Nucleosomes block the access of proteins to DNA and thus chromatin structure can modulate DNA-dependent processes such as transcription, replication, recombination, and DNA repair. Much of our insight into the role of chromatin in regulating the access of cellular machinery to DNA was driven by work with the budding yeast, Saccharomyces cerevisiae. Genetic analyses in this organism have revealed the roles played by histones and multiprotein complexes in regulating DNA-dependent processes (Rando and Winston 2012). However, although histones are among the most well-conserved proteins known, noted differences do exist between yeast and metazoan histones. First, although histone H4 is 92% conserved between S. cerevisiae and humans, H2A and H2B are less so (77 and 73% identity, respectively), which is su...

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“…Consistently, H3.3 has been found at gene bodies and promoters of transcriptionally active genes as well as gene regulatory elements, such as enhancers (1,4,5). More recently, it has been shown that the H3.3-containing nucleosomes are compromised in their ability to form compact structure in vitro and that the H3.3 genomic distribution correlates well with DNase I-sensitive regions, suggesting a preferential association with open chromatin environment in vivo (6). Interestingly, H3.3 has also been found at pericentromeric and telomeric regions, where its deposition is largely dependent on the DAXX/ATRX chaperone system; however, the function of H3.3 at these regions remains unclear (7).…”

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confidence: 61%

“…In addition, H3.3 has also been suggested to mark active chromatin (4,6). Interestingly and perhaps somewhat counterintuitively, the H3.3K36me3 reader BS69 primarily suppresses gene expression through the mechanisms discussed in BS69 Suppresses Transcription Elongation and Promotes Intron Retention.…”

Section: Bs69 Suppresses Transcription Elongation and Promotes Intronmentioning

confidence: 99%

Histone H3.3 and cancer: A potential reader connection

Lan

Shi

2014

Proc. Natl. Acad. Sci. U.S.A.

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The building block of chromatin is nucleosome, which consists of 146 base pairs of DNA wrapped around a histone octamer composed of two copies of histone H2A, H2B, H3, and H4. Significantly, the somatic missense mutations of the histone H3 variant, H3.3, are associated with childhood and young-adult tumors, such as pediatric high-grade astrocytomas, as well as chondroblastoma and giantcell tumors of the bone. The mechanisms by which these histone mutations cause cancer are by and large unclear. Interestingly, two recent studies identified BS69/ZMYND11, which was proposed to be a candidate tumor suppressor, as a specific reader for a modified form of H3.3 (H3.3K36me3). Importantly, some H3.3 cancer mutations are predicted to abrogate the H3.3K36me3/BS69 interaction, suggesting that this interaction may play an important role in tumor suppression. These new findings also raise the question of whether H3.3 cancer mutations may lead to the disruption and/or gain of interactions of additional cellular factors that contribute to tumorigenesis.histone | H3.3 | H3.3K36me3 | cancer | BS69

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H3.3 actively marks enhancers and primes gene transcription via opening higher-ordered chromatin

Cited by 207 publications

References 49 publications

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Divergent Residues Within Histone H3 Dictate a Unique Chromatin Structure in Saccharomyces cerevisiae

Histone H3.3 and cancer: A potential reader connection

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