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Title:
RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia | Nature Communications
Description:
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. Resistance to chemotherapy is a serious issue that can be influenced by RNA epigenetics and chromatin structure. Here, the authors show in leukaemia cells that RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) mediate chromatin structures that can modulate 5-Azacitidine response and resistance.
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headline:RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia
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description: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. Resistance to chemotherapy is a serious issue that can be influenced by RNA epigenetics and chromatin structure. Here, the authors show in leukaemia cells that RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) mediate chromatin structures that can modulate 5-Azacitidine response and resistance.
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name:Department of Pathology, University of Chicago, Chicago, USA
name:University of Nevada, Las Vegas, USA
name:University of Chicago Comprehensive Cancer Center, Chicago, USA
name:Department of Medicine, University of Chicago, Chicago, USA
name:University of Chicago Comprehensive Cancer Center, Chicago, USA
name:Department of Chemistry, University of Chicago, Chicago, USA
name:University of Chicago Comprehensive Cancer Center, Chicago, USA
name:Department of Medicine, University of Chicago, Chicago, USA
name:Department of Pathology, University of Chicago, Chicago, USA
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