RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.
RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.
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DOI：
10.1038/s41467-018-03513-4
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发表时间：
2018-03-21
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。对化疗的耐药性是一个严重的问题，可能受到RNA表观遗传学和染色质结构的影响。在这里，作者表明，在白血病细胞中，RNA 5-甲基胞嘧啶（RNA：m5 C）和RNA：m5 C甲基转移酶（RCMT）介导的染色质结构，可以调节5-阿扎胞苷的反应和耐药性。
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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DOI：
10.1126/science.aad8711
发表时间：
2016-06-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilbert WV;Bell TA;Schaening C
通讯作者：
Schaening C
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Ali S;Heathcote DA;Kroll SH;Jogalekar AS;Scheiper B;Patel H;Brackow J;Siwicka A;Fuchter MJ;Periyasamy M;Tolhurst RS;Kanneganti SK;Snyder JP;Liotta DC;Aboagye EO;Barrett AG;Coombes RC
通讯作者：
Coombes RC
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.9
作者：
Elhardt, Winfried;Shanmugam, Raghuvaran;Jeltsch, Albert
通讯作者：
Jeltsch, Albert