Termanis Ausma, Torrea Natalia, Culley Jayne, Kerr Alastair, Ramsahoye Bernard, Stancheva Irina
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
Nucleic Acids Res. 2016 Sep 19;44(16):7592-604. doi: 10.1093/nar/gkw424. Epub 2016 May 13.
Methylation of DNA at carbon 5 of cytosine is essential for mammalian development and implicated in transcriptional repression of genes and transposons. New patterns of DNA methylation characteristic of lineage-committed cells are established at the exit from pluripotency by de novo DNA methyltransferases enzymes, DNMT3A and DNMT3B, which are regulated by developmental signaling and require access to chromatin-organized DNA. Whether or not the capacity for de novo DNA methylation of developmentally regulated loci is preserved in differentiated somatic cells and can occur in the absence of exogenous signals is currently unknown. Here, we demonstrate that fibroblasts derived from chromatin remodeling ATPase LSH (HELLS)-null mouse embryos, which lack DNA methylation from centromeric repeats, transposons and a number of gene promoters, are capable of reestablishing DNA methylation and silencing of misregulated genes upon re-expression of LSH. We also show that the ability of LSH to bind ATP and the cellular concentration of DNMT3B are critical for cell-autonomous de novo DNA methylation in somatic cells. These data suggest the existence of cellular memory that persists in differentiated cells through many cell generations and changes in transcriptional state.
胞嘧啶碳5位的DNA甲基化对哺乳动物发育至关重要，并且与基因和转座子的转录抑制有关。在多能性退出时，由DNA从头甲基转移酶DNMT3A和DNMT3B建立了谱系定向细胞特有的新DNA甲基化模式，这些酶受发育信号调控，需要接触染色质组织的DNA。目前尚不清楚发育调控位点的从头DNA甲基化能力在分化的体细胞中是否得以保留，以及在没有外源信号的情况下是否会发生。在此，我们证明，来自染色质重塑ATP酶LSH（HELLS）基因敲除小鼠胚胎的成纤维细胞，其着丝粒重复序列、转座子和许多基因启动子缺乏DNA甲基化，在重新表达LSH后能够重新建立DNA甲基化并沉默失调基因。我们还表明，LSH结合ATP的能力和DNMT3B的细胞浓度对于体细胞中的细胞自主从头DNA甲基化至关重要。这些数据表明存在细胞记忆，它通过许多细胞世代在分化细胞中持续存在并改变转录状态。
