Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-03513-4
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Funding
- American Cancer Society [IRG-16-222-56]
- Cancer Center Support Grant of the University of Chicago Medicine Comprehensive Cancer Center [P30 CA14599]
- Swim Across America Rush University/University of Chicago
- CTSA-ITA Core Subsidies from the University of Chicago ITM grant [UL1TR002389]
- Department of Pathology, University of Chicago
- Cancer Research Foundation Young Investigator Award
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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.
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