RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia

• Type of Material: Article
• Authors: Jason X. Cheng, University of Chicago; Li Chen, University of Chicago; Yuan Li, University of Chicago; Adam Cloe, University of Chicago; Ming Yue, University of Chicago; Jiangbo Wei, University of Chicago; Kenneth Watanabe, Emory University; Jamile Shammo, Rush University; John Anastasi, University of Chicago; Qingxi J. Shen, University of Nevada; Richard A. Larson, University of Chicago; Chuan He, University of Chicago; Michelle M. Le Beau, University of Chicago; James W. Vardiman, University of Chicago
• Language: English
• Date: 2018-03-21
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-03513-4
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 1163
• End Page: 1163
• Grant/Funding Information: This study has been supported by the funding to J.X.C. from Cancer Research Foundation Young Investigator Award, an Institutional Research Grant (#IRG-16-222-56) from the American Cancer Society, the Cancer Center Support Grant (#P30 CA14599) of the University of Chicago Medicine Comprehensive Cancer Center, Swim Across America Rush University/University of Chicago, CTSA-ITA Core Subsidies from the University of Chicago ITM grant (#UL1TR002389) and research/education fund from Department of Pathology, University of Chicago.
• Keywords: Science & Technology - Other Topics; Multidisciplinary Sciences; BCR/ABL LEUKEMOGENESIS; SACCHAROMYCES-CEREVISIAE; MESSENGER-RNA; DNA-BINDING-PROTEINS; HNRNP-K; KINASE INHIBITOR; GENE; Science & Technology; POLYMERASE-II; CELLS; TRANSCRIPTION
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

The roles of RNA 5-methylcytosine (RNA:m 5 C) and RNA:m 5 C methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.1, and with CDK9/P-TEFb to recruit RNA-polymerase-II at nascent RNA, leading to formation of 5-Azacitidine (5-AZA)-sensitive chromatin structure. In contrast, NSUN1 binds BRD4 and RNA-polymerase-II to form an active chromatin structure that is insensitive to 5-AZA, but hypersensitive to the BRD4 inhibitor JQ1 and to the downregulation of NSUN1 by siRNAs. Both 5-AZA-resistant leukaemia cell lines and clinically 5-AZA-resistant myelodysplastic syndrome and acute myeloid leukaemia specimens have a significant increase in RNA:m 5 C and NSUN1-/BRD4-associated active chromatin. This study reveals novel RNA:m 5 C/RCMT-mediated chromatin structures that modulate 5-AZA response/resistance in leukaemia cells, and hence provides a new insight into treatment of leukaemia.