PAF1 regulation of promoter-proximal pause release via enhancer activation

Fei Xavier Chen, Peng Xie, Clayton K. Collings, Kaixiang Cao, Yuki Aoi, Stacy A. Marshall, Emily J. Rendleman, Michal Ugarenko, Patrick A. Ozark, Anda Zhang, Ramin Shiekhattar, Edwin Richard Smith, Michael Q. Zhang, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Gene expression in metazoans is regulated by RNA polymerase II (Pol II) promoter-proximal pausing and its release. Previously, we showed that Pol II–associated factor 1 (PAF1) modulates the release of paused Pol II into productive elongation. Here, we found that PAF1 occupies transcriptional enhancers and restrains hyperactivation of a subset of these enhancers. Enhancer activation as the result of PAF1 loss releases Pol II from paused promoters of nearby PAF1 target genes. Knockout of PAF1-regulated enhancers attenuates the release of paused Pol II on PAF1 target genes without major interference in the establishment of pausing at their cognate promoters. Thus, a subset of enhancers can primarily modulate gene expression by controlling the release of paused Pol II in a PAF1-dependent manner.

Original languageEnglish (US)
Pages (from-to)1294-1298
Number of pages5
JournalScience
Volume357
Issue number6357
DOIs
StatePublished - Sep 22 2017

Funding

We thank all the members of the Shilatifard laboratory, J. Yu, J. Crispino, J. Wang, and D. Taatjes for helpful discussions during the course of this work; I. Cheeseman for the gift of the OsTIR1-expressing DLD-1 cell line; M. Kanemaki for the gift of the pMK286 (mAID-Neo) and pMK287 (mAID-Hygro) plasmids; M. Mendillo and S. Takagishi for suggestions about CRISPR/Cas9; and L. Shilatifard for editorial assistance. ChIP-seq, RNA-seq, and 4C-seq data have been deposited at the Gene Expression Omnibus (GEO) under accession number GSE97527. Supported by NIH grant MH102616 and Natural Science Foundation of China grant 31671384 (M.Q.Z.); NIH grant CA211428 (E.R.S.); NIH grants GM078455 and GM105754 and the University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center (R.S.); a JSPS Research Fellowship for Young Scientists (Y.A.); a Eugene McDermott Graduate Fellowship (P.X.); and a Robert H. Lurie Comprehensive Cancer Center–Lefkofsky Family Foundation/Liz and Eric Lefkofsky Innovation Research Award (A.S.). Transcriptional elongation studies in the Shilatifard laboratory are supported by National Cancer Institute grant CA214035 (A.S.).

ASJC Scopus subject areas

  • General

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