The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing

Etchegaray, Jean‐Pierre; Zhong, Lei; Li, Catherine; Henriques, Telmo; Ablondi, Eileen F.; Nakadai, Tomoyoshi; Rechem, Capucine Van; Ferrer, Christina M.; Ross, Kenneth N.; Choi, Jee-Eun; Samarakkody, Ann; Ji, Fei; Chang, Andrew R.; Sadreyev, Ruslan I.; Ramaswamy, Sridhar; Nechaev, Sergei; Whetstine, Johnathan R.; Roeder, Robert G.; Adelman, Karen; Goren, Alon; Mostoslavsky, Raúl

doi:10.1016/j.molcel.2019.06.034

Cited by 52 publications

(47 citation statements)

References 107 publications

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“…In comparison, genes bound only by MYC demonstrated lower RNAPII pausing index but still retained a transcriptional level comparable to genes bound by both factors. Consistent with these findings, it has previously been shown that genetic ablation and chemical inhibition of LSD1 in pluripotent cell lines (mouse ESCs and F9 cells) increased the level of H3K56ac 64 , a histone modification associated with the gene body 2 and recently identified as a key histone mark, along with H3K9ac, that modulates transcriptional pausing and elongation 58 . In another study, LSD1 ablation and catalytic inhibition led to an upregulation of H4K16ac 64 , a histone mark that has been implicated in the regulation of RNAPII promoter-proximal pausing by recruiting BRD4 and P-TEFb 65, 66 .…”

Section: Discussionsupporting

confidence: 65%

“…The co-localization of LSD1 and CDK9 was observed at both promoter and enhancer elements, where CDK9 have been shown to be involved in enhancer-associated RNAPII pausing 17, 56, 57 . A recent study has demonstrated a functional role of SIRT6, a histone deacetylase, in the release of RNAPII pausing by preventing the eviction of NELF-E from the chromatin 58 , highlighting the direct involvement of chromatin remodellers in RNAPII pausing and release.…”

Section: Discussionmentioning

confidence: 99%

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Integrative Analysis Reveals Histone Demethylase LSD1/KDM1A Associates with RNA Polymerase II Pausing

Kim

Oldfield

et al. 2020

Preprint

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RNA polymerase II (RNAPII) pausing at gene promoters is a rate-limiting step in transcription regulation. Previous studies have elucidated the coordinated actions of pausing and releasing factors that collectively modulate RNAPII pausing. In general, the involvement of chromatin remodellers in RNAPII pausing has not been well documented. Whilst LSD1 is well-known for its role in decommissioning enhancers during ESC differentiation, its role at the promoters of genes remains poorly understood despite their widespread presence at these sites. Here, we report that LSD1 is associated with RNAPII pausing at the promoter-proximal region of genes in mouse embryonic stem cells (ESCs). We demonstrate that the knockdown of LSD1 preferentially affects genes with higher RNAPII pausing than those with lower pausing and, importantly, show that the co-localization of LSD1 and MYC, a factor known to regulate pause-release, is associated with the enrichment of other RNAPII pausing factors compared to their independent counterparts. Moreover, we found that genes co-occupied by LSD1 and MYC are significantly enriched for housekeeping genes that are involved in metabolic processes and globally depleted of transcription factors compared to those bound only by LSD1. These findings reveal a pleiotropic role of LSD1 in regulating housekeeping program besides its previously known role in regulating cell identity programs. Our integrative analysis presents evidence for a previously unanticipated role of LSD1 in RNAPII pausing through its association with pause release factors in modulating cell-type specific and cell-type invariant genes.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Integrative Analysis Reveals Histone Demethylase LSD1/KDM1A Associates with RNA Polymerase II Pausing

Kim

Oldfield

et al. 2020

Preprint

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“…The ChIP data is presented as log 2 (ChIP/input) as nucleosome density is not consistent between the different gene bins. h The average signal relative to the TSS for PRO-seq 74 , and H3K9ac and H3K27ac ChIP-seq data relative to all genes (green) or 3035 transcribed genes that have low (blue) or high (red) upstream PRO-seq signal. …”

Section: Resultsmentioning

confidence: 99%

Transcription shapes genome-wide histone acetylation patterns

et al. 2021

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Histone acetylation is a ubiquitous hallmark of transcription, but whether the link between histone acetylation and transcription is causal or consequential has not been addressed. Using immunoblot and chromatin immunoprecipitation-sequencing in S. cerevisiae, here we show that the majority of histone acetylation is dependent on transcription. This dependency is partially explained by the requirement of RNA polymerase II (RNAPII) for the interaction of H4 histone acetyltransferases (HATs) with gene bodies. Our data also confirms the targeting of HATs by transcription activators, but interestingly, promoter-bound HATs are unable to acetylate histones in the absence of transcription. Indeed, HAT occupancy alone poorly predicts histone acetylation genome-wide, suggesting that HAT activity is regulated post-recruitment. Consistent with this, we show that histone acetylation increases at nucleosomes predicted to stall RNAPII, supporting the hypothesis that this modification is dependent on nucleosome disruption during transcription. Collectively, these data show that histone acetylation is a consequence of RNAPII promoting both the recruitment and activity of histone acetyltransferases.

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“…SIRT6 can also bind p53 to effectively recruit RNAP2 to local promoters ( Li et al, 2018 ). SIRT6 deficiency mediates the activation of cyclin-dependent kinase 9 (CDK9) that can phosphorylate negative elongation factor (NELF) and mediate NELF release from RNAP2, facilitating the enrichment of TFs and RNAP2-related elongation factors to promote elongation of specific gene sets ( Etchegaray et al, 2019 ). Consistently, TSA and SAHA disturb RNAP2-mediated transcriptional elongation by promoting the association between RNAP2 and NELF ( Greer et al, 2015 ).…”

Section: Biological Functions Of Hdacsmentioning

confidence: 99%

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Guo

Tian

Zhu

2020

Front. Cell Dev. Biol.

181

135

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Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (N ε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

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The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing

Cited by 52 publications

References 107 publications

Integrative Analysis Reveals Histone Demethylase LSD1/KDM1A Associates with RNA Polymerase II Pausing

Integrative Analysis Reveals Histone Demethylase LSD1/KDM1A Associates with RNA Polymerase II Pausing

Transcription shapes genome-wide histone acetylation patterns

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

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