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University of Texas Health Science Center at Houston

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Mol. Cell, Available online 9 August 2021 | https://doi.org/10.1016/j.molcel.2021.07.024 Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation

Joo-Hyung Lee,^1,11 Ruoyu Wang,^1,2,11 Feng Xiong,^1,11 Joanna Krakowiak,¹ Zian Liao,^1,2 Phuoc T. Nguyen,^1,2 Elena V. Moroz-Omori,³ Jiaofang Shao,¹ Xiaoyu Zhu,¹ Michael J. Bolt,^4,5 Haoyi Wu,^1,2 Pankaj K. Singh,^4,5 Mingjun Bi,⁶ Caleb J. Shi,¹ Naadir Jamal,¹ Guojie Li,¹ Ragini Mistry,^5,9 Sung Yun Jung,⁷ Kuang-Lei Tsai,¹ Josephine C. Ferreon,⁸ Fabio Stossi,^5,9 Amedeo Caflisch,³ Zhijie Liu,⁶ Michael A. Mancini,^4,5,8,9,10 and Wenbo Li^1,2,12,*

¹Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA ²Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center and UTHealth, Houston, TX 77030, USA ³Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland ⁴Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA ⁵Gulf Coast Consortia Center for Advanced Microscopy and Image Informatics, Houston, TX 77030, USA ⁶Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA ⁷Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA ⁸Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA ⁹Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA ¹⁰Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA ¹¹These authors contributed equally ¹²Lead contact

^*Correspondence

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.

논문정보

형식Research article
게재일2021년 08월 (BRIC 등록일 2021-08-17)
연구진국외 연구진
분야 생명과학 > 분자생물학

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