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

Jason X. Cheng (), Li Chen, Yuan Li, Adam Cloe, Ming Yue, Jiangbo Wei, Kenneth A. Watanabe, Jamile M. Shammo, John Anastasi, Qingxi J. Shen, Richard A. Larson, Chuan He, Michelle M. Beau and James W. Vardiman
Additional contact information
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 A. Watanabe: Emory University
Jamile M. Shammo: Rush University Medical Center
John Anastasi: University of Chicago
Qingxi J. Shen: University of Nevada
Richard A. Larson: University of Chicago Comprehensive Cancer Center
Chuan He: University of Chicago Comprehensive Cancer Center
Michelle M. Beau: University of Chicago Comprehensive Cancer Center
James W. Vardiman: University of Chicago

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract The roles of RNA 5-methylcytosine (RNA:m5C) and RNA:m5C 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:m5C and NSUN1-/BRD4-associated active chromatin. This study reveals novel RNA:m5C/RCMT-mediated chromatin structures that modulate 5-AZA response/resistance in leukaemia cells, and hence provides a new insight into treatment of leukaemia.

Date: 2018
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DOI: 10.1038/s41467-018-03513-4

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