R loops regulate promoter-proximal chromatin architecture and cellular differentiation
Department of Molecular, Cell and Cancer Biology; Department of Biochemistry and Molecular Pharmacology; Program in Molecular Medicine
Biochemistry | Cell Biology | Molecular Biology
Numerous chromatin-remodeling factors are regulated by interactions with RNA, although the contexts and functions of RNA binding are poorly understood. Here we show that R loops, RNA-DNA hybrids consisting of nascent transcripts hybridized to template DNA, modulate the binding of two key chromatin-regulatory complexes, Tip60-p400 and polycomb repressive complex 2 (PRC2) in mouse embryonic stem cells (ESCs). Like PRC2, the Tip60-p400 histone acetyltransferase complex binds to nascent transcripts; however, transcription promotes chromatin binding of Tip60-p400 but not PRC2. Interestingly, we observed higher Tip60-p400 and lower PRC2 levels at genes marked by promoter-proximal R loops. Furthermore, disruption of R loops broadly decreased Tip60-p400 occupancy and increased PRC2 occupancy genome wide. In agreement with these alterations, ESCs partially depleted of R loops exhibited impaired differentiation. These results show that R loops act both positively and negatively in modulating the recruitment of key pluripotency regulators.
DOI of Published Version
Nat Struct Mol Biol. 2015 Dec;22(12):999-1007. doi: 10.1038/nsmb.3122. Epub 2015 Nov 9. Link to article on publisher's site
Nature structural and molecular biology
Chen, Poshen B.; Chen, Hsiuyi V.; Acharya, Diwash; Rando, Oliver J.; and Fazzio, Thomas G., "R loops regulate promoter-proximal chromatin architecture and cellular differentiation" (2015). Molecular, Cell and Cancer Biology Publications. 55.