1] Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA [3] Università Cattolica del Sacro Cuore, Institute of Hematology, L.go A. Gemelli 8, Rome 00168, Italy [4].
Nature. 2013 Nov 21;503(7476):371-6. doi: 10.1038/nature12598. Epub 2013 Oct 9.
DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extend the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1-RNA interactions and suggest strategies for gene-selective demethylation of therapeutic targets in human diseases.
DNA 甲基化在近一个世纪前就已被首次描述，但调控其建立和维持的规则仍难以捉摸。在这里，我们呈现的数据表明，活跃的转录可调控基因组甲基化水平。我们鉴定出一种源自 CEBPA 基因座的新型 RNA，它在调控局部 DNA 甲基化图谱方面至关重要。这种 RNA 与 DNMT1 结合，防止 CEBPA 基因座甲基化。与 DNMT1 相关的转录物的深度测序，结合全基因组的甲基化和表达谱分析，将这一发现的普遍性扩展到许多基因座。总的来说，这些结果描绘了 DNMT1-RNA 相互作用的本质，并为人类疾病中治疗靶点的基因选择性去甲基化提供了策略。
