Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29261-0
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Funding
- FONDECYT Regular Grant [1191152, 1171004]
- CONICYT/ANID Ph.D. Fellowship [21161044, 21140438]
- CONICYT/ANID FONDECYT Postdoctoral Grant [3160308]
- FRAXA grant
- N.I.H grant [R01HD097665]
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RCOR1 is paradoxically enriched in transcriptionally active chromatin and represses transcription through two mechanisms.
The classical neuronal-gene corepressor RCOR1/CoREST is paradoxically enriched in transcriptionally active chromatin. Here the authors show RCOR1 is recruited during promoter-proximal pausing and negatively regulates the nascent-transcript synthesis. They also show that an RCOR1-LSD1- HDAC1 complex removes lysine acetylation from RNA polymerase II to repress transcription. RCOR1 is a known transcription repressor that recruits and positions LSD1 and HDAC1/2 on chromatin to erase histone methylation and acetylation. However, there is currently an incomplete understanding of RCOR1's range of localization and function. Here, we probe RCOR1's distribution on a genome-wide scale and unexpectedly find that RCOR1 is predominantly associated with transcriptionally active genes. Biochemical analysis reveals that RCOR1 associates with RNA Polymerase II (POL-II) during transcription and deacetylates its carboxy-terminal domain (CTD) at lysine 7. We provide evidence that this non-canonical RCOR1 activity is linked to dampening of POL-II productive elongation at actively transcribing genes. Thus, RCOR1 represses transcription in two ways-first, via a canonical mechanism by erasing transcriptionally permissive histone modifications through associating with HDACs and, second, via a non-canonical mechanism that deacetylates RNA POL-II's CTD to inhibit productive elongation. We conclude that RCOR1 is a transcription rheostat.
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