Tahiliani Mamta, Koh Kian Peng, Shen Yinghua, Pastor William A, Bandukwala Hozefa, Brudno Yevgeny, Agarwal Suneet, Iyer Lakshminarayan M, Liu David R, Aravind L, Rao Anjana
Department of Pathology, Harvard Medical School and Immune Disease Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
Science. 2009 May 15;324(5929):930-5. doi: 10.1126/science.1170116. Epub 2009 Apr 16.
DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference-mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.
DNA胞嘧啶甲基化对于逆转座子沉默和哺乳动物发育至关重要。在一次对能够修饰5-甲基胞嘧啶(5mC)的酶的计算机搜索中,我们鉴定出TET蛋白是锥虫蛋白JBP1和JBP2的哺乳动物同源物,有人提出JBP1和JBP2可氧化胸腺嘧啶的5-甲基基团。我们在此表明,急性髓性白血病中MLL基因的融合伴侣TET1是一种依赖2-酮戊二酸(2OG)和亚铁离子(Fe(II))的酶,它在培养细胞和体外催化5mC转化为5-羟甲基胞嘧啶(hmC)。hmC存在于小鼠胚胎干细胞的基因组中,并且在RNA干扰介导的TET1缺失时hmC水平降低。因此,TET蛋白可能通过将5mC修饰为hmC在表观遗传调控中发挥作用。