A Role for FACT in RNA Polymerase II Promoter-Proximal Pausing

Tettey, Theophilus T.; Gào, Xin; Shao, Wanqing; Li, Hua; Story, Benjamin A.; Chitsazan, Alex; Glaser, Robert L.; Goode, Zach; Seidel, Christopher; Conaway, Ronald C.; Zeitlinger, Julia; Blanchette, Marco; Conaway, Joan Weliky

doi:10.1016/j.celrep.2019.05.099

Cited by 46 publications

(49 citation statements)

References 62 publications

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“…Thus, the observed, low H3K36me3 signal indicates weak transcription elongation at genes with unstable Pol II, consistent with PRO-seq data. Conversely, genes with stable pausing exhibited stronger transcription activity and higher levels of H3K36me3 (Figures 1A and 1B), in agreement with recent work (Tettey et al, 2019).…”

Section: Resultssupporting

confidence: 92%

The Integrator Complex Attenuates Promoter-Proximal Transcription at Protein-Coding Genes

et al. 2019

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The transition of RNA polymerase II (Pol II) from initiation to productive elongation is a central, regulated step in metazoan gene expression. At many genes, Pol II pauses stably in early elongation, remaining engaged with the 25-to 60-nt-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, 15%-20% of genes display highly unstable promoter Pol II, suggesting that paused polymerase might dissociate from template DNA at these promoters and release a short, non-productive mRNA. Here, we report that paused Pol II can be actively destabilized by the Integrator complex. Specifically, we present evidence that Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive termination of paused Pol II. These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination.

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Section: Resultssupporting

confidence: 92%

The Integrator Complex Attenuates Promoter-Proximal Transcription at Protein-Coding Genes

et al. 2019

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“…The activation of MERVL-fused genes meant these genes need to switch from canonical promoters to MERVL-derived cryptic promoters (Figure 4E ). FACT interacts with RNA polymerase II (Figure 5A and Supplementary Table S5 ) and maintains RNA polymerase II pausing at the proximal promoter region ( 80 ), which prevents downstream cryptic transcription initiation ( 81 ). Besides MERVL, other TEs are capable to work as cryptic promoters to drive expression of oncogenes in human cancers ( 37 ), implying a potential role of FACT and other repressors of cryptic transcription in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters

Chen

Zhang

Xie

et al. 2020

Nucleic Acids Research

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Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.

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“…Recent studies showed that the histone chaperones Spt6 and FACT (composed of Spt16 and Pob3) are also required for the normal distribution of several histone modifications, as shifts toward the 3′ end occurred in yeast spt6 and spt16 mutants ( 95 ), as well as after depletion of FACT in Drosophila cells ( 97 ). The yeast study suggested that these shifts were a consequence of transcription-dependent loss of histones on chromatin due to impaired nucleosome reassembly in the wake of transcription.…”

Section: Discussionmentioning

confidence: 99%

The conserved elongation factor Spn1 is required for normal transcription, histone modifications, and splicing in Saccharomyces cerevisiae

Reim

Chuang

Jain

et al. 2020

Nucleic Acids Research

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Spn1/Iws1 is a conserved protein involved in transcription and chromatin dynamics, yet its general in vivo requirement for these functions is unknown. Using a Spn1 depletion system in Saccharomyces cerevisiae, we demonstrate that Spn1 broadly influences several aspects of gene expression on a genome-wide scale. We show that Spn1 is globally required for normal mRNA levels and for normal splicing of ribosomal protein transcripts. Furthermore, Spn1 maintains the localization of H3K36 and H3K4 methylation across the genome and is required for normal histone levels at highly expressed genes. Finally, we show that the association of Spn1 with the transcription machinery is strongly dependent on its binding partner, Spt6, while the association of Spt6 and Set2 with transcribed regions is partially dependent on Spn1. Taken together, our results show that Spn1 affects multiple aspects of gene expression and provide additional evidence that it functions as a histone chaperone in vivo.

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A Role for FACT in RNA Polymerase II Promoter-Proximal Pausing

Abstract: Highlights d FACT regulates patterns of transcription-coupled histone marks d FACT knockdown reduces the half-life of promoterproximally paused Pol II d FACT helps to maintain promoter-proximal Pol II pausing

Cited by 46 publications

References 62 publications

The Integrator Complex Attenuates Promoter-Proximal Transcription at Protein-Coding Genes

The Integrator Complex Attenuates Promoter-Proximal Transcription at Protein-Coding Genes

Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters

The conserved elongation factor Spn1 is required for normal transcription, histone modifications, and splicing in Saccharomyces cerevisiae

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