Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation

TitleEnhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation
Publication TypeJournal Article
Year of Publication2021
AuthorsLee J.-H., Wang R., Xiong F., Krakowiak J., Liao Z., Nguyen P.T, Moroz-Omori E.V, Shao J., Zhu X., Bolt M.J, Wu H., Singh P.K, Bi M., Shi C.J, Jamal N., Li G., Mistry R., Jung S.Y, Tsai K.-L., Ferreon J.C, Stossi F., Caflisch A., Liu Z., Mancini M.A, Li W.
JournalMolecular Cell
Volume81
Issue16
Pagination3368-3385.e9
Date Published2021 08 19
Type of ArticleResearch Article
KeywordsAdenosine, Cell Cycle Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Methylation, Nerve Tissue Proteins, Regulatory Elements, Transcriptional, RNA, RNA Splicing Factors, Transcription Factors, Transcriptional Activation
Abstract

The mechanistic understanding of nascent RNAs in transcriptional control remains limited. Here, by a high sensitivity method methylation-inscribed nascent transcripts sequencing (MINT-seq), we characterized the landscapes of N6-methyladenosine (m6A) on nascent RNAs. We uncover heavy but selective m6A deposition on nascent RNAs produced by transcription regulatory elements, including promoter upstream antisense RNAs and enhancer RNAs (eRNAs), which positively correlates with their length, inclusion of m6A motif, and RNA abundances. m6A-eRNAs mark highly active enhancers, where they recruit nuclear m6A reader YTHDC1 to phase separate into liquid-like condensates, in a manner dependent on its C terminus intrinsically disordered region and arginine residues. The m6A-eRNA/YTHDC1 condensate co-mixes with and facilitates the formation of BRD4 coactivator condensate. Consequently, YTHDC1 depletion diminished BRD4 condensate and its recruitment to enhancers, resulting in inhibited enhancer and gene activation. We propose that chemical modifications of eRNAs together with reader proteins play broad roles in enhancer activation and gene transcriptional control.

DOI10.1016/j.molcel.2021.07.024
pubindex

0272

Alternate JournalMol. Cell
PubMed ID34375583
PubMed Central IDPMC8383322
Grant ListR21 GM132778 / GM / NIGMS NIH HHS / United States
R01 GM122763 / GM / NIGMS NIH HHS / United States
UL1 TR003167 / TR / NCATS NIH HHS / United States
U01 HL156059 / HL / NHLBI NIH HHS / United States
P30 DK056338 / DK / NIDDK NIH HHS / United States
R01 GM137009 / GM / NIGMS NIH HHS / United States
R01 GM136922 / GM / NIGMS NIH HHS / United States
K22 CA204468 / CA / NCI NIH HHS / United States
P30 ES030285 / ES / NIEHS NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States