H2B monoubiquitylation is a 5′-enriched active transcription mark and correlates with exon–intron structure in human cells

Jung, Inkyung; Kim, Seung-Kyoon; Kim, Mirang; Han, Yong‐Mahn; Kim, Yong‐Sung; Kim, Dongsup; Lee, Daeyoup

doi:10.1101/gr.120634.111

Cited by 63 publications

(72 citation statements)

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“…Huff et al (2010) showed that H2Bub1 levels decrease following the first internal exon, while Jung et al (2012) reported that H2Bub1 is mainly enriched at exon borders. Our analysis of H2Bub1 distribution in NT2 and HCT116 cells agrees with the reported reduction in H2Bub1 after the first internal exon but extends this notion by showing that exons downstream from the first internal exon are associated with stepwise drops in H2Bub1.…”

Section: Discussionmentioning

confidence: 99%

“…While one study reported that H2Bub1 is significantly reduced following the first internal exon (Huff et al 2010), another study concluded that H2Bub1 is selectively enriched at exon-intron borders and proposed that this enrichment regulates the splicing of a subset of exons (Jung et al 2012).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…H2Bub1 regulates multiple molecular processes such as transcription initiation and elongation (Davie and Murphy 1990;Henry et al 2003;Pavri et al 2006;Weinberger et al 2012), DNA damage response (Chernikova et al 2010;Kari et al 2011;Moyal et al 2011;Nakamura et al 2011), DNA replication (Trujillo and Osley 2012), nucleosome positioning (Batta et al 2011), and RNA processing and export (Pirngruber et al 2009;Jung et al 2012;Moehle et al 2012;Vitaliano-Prunier et al 2012;Herissant et al 2014;Long et al 2014). Aberrant H2Bub1 levels can affect development (Wright et al 2011), apoptosis (Walter et al 2010), stem cell differentiation (Buszczak et al 2009;Fuchs et al 2012;Karpiuk et al 2012), viral infection outcome (Sarkari et al 2009;Fonseca et al 2012), and cell cycle progression (Hwang and Madhani 2009) and can promote cancer Blank et al 2012;Johnsen 2012;.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

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Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

et al. 2014

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Various histone modifications decorate nucleosomes within transcribed genes. Among these, monoubiquitylation of histone H2B (H2Bub1) and methylation of histone H3 on lysines 36 (H3K36me2/3) and 79 (H3K79me2/3) correlate positively with gene expression. By measuring the progression of the transcriptional machinery along genes within live cells, we now report that H2B monoubiquitylation occurs cotranscriptionally and accurately reflects the advance of RNA polymerase II (Pol II). In contrast, H3K36me3 and H3K79me2 are less dynamic and represent Pol II movement less faithfully. High-resolution ChIP-seq reveals that H2Bub1 levels are selectively reduced at exons and decrease in an exon-dependent stepwise manner toward the 39 end of genes. Exonic depletion of H2Bub1 in gene bodies is highly correlated with Pol II pausing at exons, suggesting elongation rate changes associated with intron-exon structure. In support of this notion, H2Bub1 levels were found to be significantly correlated with transcription elongation rates measured in various cell lines. Overall, our data shed light on the organization of H2Bub1 within transcribed genes and single out H2Bub1 as a reliable marker for ongoing transcription elongation.

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Section: Discussionmentioning

confidence: 99%

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

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Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

et al. 2014

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“…22,23 H2Bub is often enriched in the promoter region of actively transcriptional genes in both yeast and mammalian somatic cells. 18,[24][25][26] Previously, it was found that the knockout of Rad6 mammalian homolog, HR6B, results in male infertility due to defect in spermatogenesis. Detailed analysis of the knockout mice revealed that the synaptonemal complex and meiotic recombination were affected in the spermatocytes, thus strongly implicate the role of H2Bub in chromatin remodeling.…”

Section: Conserved Functions Of H2bub During Meiosismentioning

confidence: 99%

H2B ubiquitination: Conserved molecular mechanism, diverse physiologic functions of the E3 ligase during meiosis

Wang

Cao

Wang

et al. 2017

Nucleus

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RNF20/Bre1 mediated H2B ubiquitination (H2Bub) has various physiologic functions. Recently, we found that H2Bub participates in meiotic recombination by promoting chromatin relaxation during meiosis. We then analyzed the phylogenetic relationships among the E3 ligase for H2Bub, its E2 Rad6 and their partner WW domain-containing adaptor with a coiled-coil (WAC) or Lge1, and found that the molecular mechanism underlying H2Bub is evolutionarily conserved from yeast to mammals. However, RNF20 has diverse physiologic functions in different organisms, which might be caused by the evolutionary divergency of their domain/motif architectures. In the current extra view, we not only elucidate the evolutionarily conserved molecular mechanism underlying H2Bub, but also discuss the diverse physiologic functions of RNF20 during meiosis.

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“…H2B-Ub is enriched near the 5′ end of highly expressed genes and has been implicated in transcriptional elongation, as well as chromatin structure definition (6)(7)(8)(9). Moreover, H2B-Ub directly regulates the H3K4 and H3K79 methyltransferases Set1 and Dot1, respectively (10)(11)(12)(13).…”

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Identification of a functional hotspot on ubiquitin required for stimulation of methyltransferase activity on chromatin

Holt

David

Pollock

et al. 2015

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

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Ubiquitylation of histone H2B at lysine 120 (H2B-Ub) plays a critical role in transcriptional elongation, chromatin conformation, as well as the regulation of specific histone H3 methylations. Herein, we report a strategy for the site-specific chemical attachment of ubiquitin to preassembled nucleosomes. This allowed expedited structure-activity studies into how H2B-Ub regulates H3K79 methylation by the methyltransferase human Dot1. Through an alanine scan of the ubiquitin surface, we identified a functional hotspot on ubiquitin that is required for the stimulation of human Dot1 in vitro. Importantly, this result was validated in chromatin from isolated nuclei by using a synthetic biology strategy that allowed selective incorporation of the hotspot-deficient ubiquitin mutant into H2B. The ubiquitin hotspot additionally impacted the regulation of ySet1-mediated H3K4 methylation but was not required for H2B-Ub-induced impairment of chromatin fiber compaction. These data demonstrate the utility of applying chemical ligation technologies to preassembled chromatin and delineate the multifunctionality of ubiquitin as a histone posttranslational modification.H istone posttranslational modifications (PTMs) modulate chromatin structure and function either by directly altering the intrinsic physical properties of the chromatin fiber or by nucleating the recruitment and activity of a host of transacting nuclear factors (1-3). The chemical diversity, differential dynamics, and sheer number (currently over 100) (4, 5) of these PTMs, along with their combinatorial occurrence at the level of the nucleosome, create a complex and nonstatic molecular architecture in which all chromatin-related processes function. A central challenge in the field of epigenetics is to disentangle how distinct chromatin states control biochemical outputs, which requires the elucidation of the critical determinants governing histone PTM readout.A particularly fascinating histone PTM is the ubiquitylation of H2B at lysine 120 (H2B-Ub). H2B-Ub is enriched near the 5′ end of highly expressed genes and has been implicated in transcriptional elongation, as well as chromatin structure definition (6-9). Moreover, H2B-Ub directly regulates the H3K4 and H3K79 methyltransferases Set1 and Dot1, respectively (10-13). The mechanistic principles underlying these various phenomena remain poorly understood. At 8.5 kDa, ubiquitin is nearly as large as the histone to which it is linked (13.8 kDa in the case of H2B), increasing the nucleosome surface by as much as 4,800 A 2 (14). Thus, compared with smaller PTMs such as acetylation and methylation, ubiquitin is "information rich" in that it alters the steric and electrostatic properties around its attachment site, as well as presenting a large surface area for the recruitment of binding factors. Structural and biochemical studies of ubiquitin-ligand complexes, including the ubiquitylation of histone H2A at lysine 15, have revealed a canonical binding hotspot on ubiquitin involving a hydrophobic patch centered on Leu8/I...

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H2B monoubiquitylation is a 5′-enriched active transcription mark and correlates with exon–intron structure in human cells

Cited by 63 publications

References 50 publications

Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

H2B ubiquitination: Conserved molecular mechanism, diverse physiologic functions of the E3 ligase during meiosis

Identification of a functional hotspot on ubiquitin required for stimulation of methyltransferase activity on chromatin

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