The PAF1 complex promotes 3′ processing of pervasive transcripts

Liu, Xinhong; Guo, Ziwei; Han, Jing; Peng, Bo; Zhang, Bin; Li, Haitao; Hu, Xiaoyu; David, Charles J.; Chen, Mo

doi:10.1016/j.celrep.2022.110519

Cited by 25 publications

(22 citation statements)

References 107 publications

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“…Structural comparison of NELF- and PAF1C-containing Pol II complexes reveals steric clashes between NELF and PAF1C, thus eliciting a plausible model that the shift of Pol II from the first to the second pausing sites is accompanied by a substantial change in the composition of Pol II complex, such as the replacement of NELF by PAF1C [ 15 , 54 , 58 ]. Different from the eviction of NELF during this transition, DSIF remains with Pol II at the second pausing site ( Figure 2a ).…”

Section: Spt5 Function In Pausingmentioning

confidence: 99%

“…Therefore, loss of INTAC phosphatase activity confers cellular resistance to P-TEFb inhibition ( Figure 3b ) [ 77 ]. The balance between P-TEFb and INTAC in modulating pausing and pause release could be harnessed by other transcription regulators such as PAF1C, which can directly interact with INTAC [ 54 , 58 ]. Through this interaction, PAF1 can recruit INTAC to genomic regions, including promoters, to suppress SPT5 phosphorylation, which could potentially explain the broad function of PAF1 in restraining the release of Pol II from the second pausing sites [ 54–56 ].…”

Section: Targeting Spt5 By Phosphatasesmentioning

confidence: 99%

“…Nonetheless, the regulation of pause release by SPT5 phosphorylation status at enhancers is poorly investigated. We surmise that the balance between P-TEFb and INTAC in modulating pausing and pause release, partially by controlling SPT5 phosphorylation as discussed above [ 76–78 ], is also in play at enhancers as promoters do, because PAF1-dependent INTAC recruitment at enhancers prevents the release of paused Pol II and eRNA accumulation [ 54 , 56 , 58 ]. In addition to the INTAC phosphatase module, the RNA endonuclease activity in the Integrator module of INTAC could additionally promote termination to suppress enhancer transcription [ 58 , 143 , 144 ].…”

Section: Enhancer Regulation By Spt5mentioning

confidence: 99%

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The pleiotropic roles of SPT5 in transcription

Song

Chen

2022

Transcription

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Initially discovered by genetic screens in budding yeast, SPT5 and its partner SPT4 form a stable complex known as DSIF in metazoa, which plays pleiotropic roles in multiple steps of transcription. SPT5 is the most conserved transcription elongation factor, being found in all three domains of life; however, its structure has evolved to include new domains and associated posttranslational modifications. These gained features have expanded transcriptional functions of SPT5, likely to meet the demand for increasingly complex regulation of transcription in higher organisms. This review discusses the pleiotropic roles of SPT5 in transcription, including RNA polymerase II (Pol II) stabilization, enhancer activation, Pol II pausing and its release, elongation, and termination, with a focus on the most recent progress of SPT5 functions in regulating metazoan transcription.

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Section: Spt5 Function In Pausingmentioning

confidence: 99%

Section: Targeting Spt5 By Phosphatasesmentioning

confidence: 99%

Section: Enhancer Regulation By Spt5mentioning

confidence: 99%

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The pleiotropic roles of SPT5 in transcription

Song

Chen

2022

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“…H3K4me2 and H3K4me3 induces a relative enrichment of promoter-bound INTAC complex, which has recently been found to be a major regulator of premature promoter-proximal termination in higher organisms (75,96,(98)(99)(100)(101)(102)(103)(104)(105)(106). However, it is still unclear whether H3K4me2 and H3K4me3 regulate pausing directly through modulating chromatin structure or by recruiting effector proteins implicated in paused Pol II stability.…”

Section: Discussionmentioning

confidence: 99%

H3K4 di- and trimethylation modulate the stability of RNA polymerase II pausing

Song

Peng

et al. 2022

Preprint

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SUMMARYModifications of histones are intricately linked with the regulation of gene expression, with demonstrated roles in various physiological processes and disease pathogenesis. Methylation of histone H3 lysine 4 (H3K4), implemented by the COMPASS family, is enriched at promoters and associated cis-regulatory elements, with H3K4 trimethylation (H3K4me3) considered a hallmark of active gene promoters. However, the relative roles of deposition and removal of H3K4 methylation, as well as the extent to which these events contribute to transcriptional regulation have so far remained unclear. Here, through rapid depletion of the transcription regulator SPT5 or either of two shared subunits of COMPASS family members, we reveal a dynamic turnover of H3K4me3 mediated by the KDM5 family of histone demethylases. Loss of H3K4me3 following COMPASS disruption does not impair the recruitment of TFIID and initiating RNA polymerase II (Pol II). Instead, H3K4me3 loss leads to reductions in the paused form of Pol II on chromatin while inducing the relative enrichment of the Integrator-PP2A (INTAC) termination complex, leading to reduced levels of elongating polymerases, thus revealing how H3K4me3 dynamics can regulate Pol II pausing to sustain or attenuate transcription.

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“…They are rapidly degraded by the nuclear exosome complex after 3′ endonucleolytic cleavage by the Integrator complex (Integrator) approximately 1-3 kb downstream of the transcription start site. Notably, PAF1C (polymerase-associated factor 1 complex) has a role in termination of eRNAs by facilitating recruitment of Integrator (Li W. et al, 2016;Liu et al, 2022). At the same time, enhancers can also initiate transcription of lncRNA, frequently in the antisense direction to the coding gene in the same locus.…”

Section: Enhancer Rnasmentioning

confidence: 99%

Natural antisense transcripts as drug targets

Khorkova

Stahl

Joji

et al. 2022

Front. Mol. Biosci.

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The recent discovery of vast non-coding RNA-based regulatory networks that can be easily modulated by nucleic acid-based drugs has opened numerous new therapeutic possibilities. Long non-coding RNA, and natural antisense transcripts (NATs) in particular, play a significant role in networks that involve a wide variety of disease-relevant biological mechanisms such as transcription, splicing, translation, mRNA degradation and others. Currently, significant efforts are dedicated to harnessing these newly emerging NAT-mediated biological mechanisms for therapeutic purposes. This review will highlight the recent clinical and pre-clinical developments in this field and survey the advances in nucleic acid-based drug technologies that make these developments possible.

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The PAF1 complex promotes 3′ processing of pervasive transcripts

Cited by 25 publications

References 107 publications

The pleiotropic roles of SPT5 in transcription

The pleiotropic roles of SPT5 in transcription

H3K4 di- and trimethylation modulate the stability of RNA polymerase II pausing

Natural antisense transcripts as drug targets

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