Author Correction: RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.
Author Correction: RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.
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DOI：
10.1038/s41467-018-04518-9
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发表时间：
2018-06-06
影响因子：
16.6
通讯作者：
Vardiman JW
中科院分区：
文献类型：
--
作者：
Cheng JX;Chen L;Li Y;Cloe A;Yue M;Wei J;Watanabe KA;Shammo JM;Anastasi J;Shen QJ;Larson RA;He C;Le Beau MM;Vardiman JW
RNA 5-甲基胞嘧啶（RNA：m5 C）和RNA：m5 C甲基转移酶（RCMT）在谱系相关染色质组织和药物反应/耐药性中的作用尚不清楚。在这里，我们证明了RCMT，即NSUN 3和DNMT 2，直接结合hnRNPK，一种保守的RNA结合蛋白。hnRNPK与谱系决定转录因子（TF）、GATA 1和SPI 1/PU. 1以及CDK 9/P-TEFb相互作用，在新生RNA上募集RNA聚合酶II，从而形成5-阿扎胞苷（5-AZA）敏感的染色质结构。相反，NSUN 1结合BRD 4和RNA聚合酶II以形成活性染色质结构，其对5-AZA不敏感，但对BRD 4抑制剂JQ 1和siRNA下调NSUN 1超敏感。5-AZA耐药白血病细胞系和临床5-AZA耐药骨髓增生异常综合征和急性髓性白血病标本的RNA：m5 C和NSUN 1-/BRD 4相关活性染色质均显著增加。这项研究揭示了新的RNA：m5 C/RCMT介导的染色质结构，调节白血病细胞中的5-AZA反应/抗性，从而为白血病的治疗提供了新的见解。
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.
影响因子：
16.6
作者：
Cheng JX;Chen L;Li Y;Cloe A;Yue M;Wei J;Watanabe KA;Shammo JM;Anastasi J;Shen QJ;Larson RA;He C;Le Beau MM;Vardiman JW
通讯作者：
Vardiman JW