Basu Amitava, Tomar Archana, Dasari Vasanthi, Mishra Rakesh Kumar, Khosla Sanjeev
Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
Graduate Studies, Manipal University, Manipal, India.
Sci Rep. 2016 Jan 22;6:19572. doi: 10.1038/srep19572.
DNMT3L is an important epigenetic regulator in mammals, integrating DNA methylation and histone modification based epigenetic circuits. Here we show DNMT3L to be a part of the machinery that enables inheritance of epigenetic modifications from one generation to the next. Ectopic expression of DNMT3L in Drosophila, which lacks DNMT3L and its normal interacting partners DNMT3A and DNMT3B, lead to nuclear reprogramming that was gradual and progressive, resulting in melanotic tumors that were observed only when these flies were maintained for five generations. This global gene expression misregulation was accompanied by aberrations in the levels of H3K4me3 and H3K36me3, globally as well as at specific gene promoters. The levels of these epigenetic aberrations (epimutations) also increased progressively across successive generations. The accumulation and inheritance of epimutations across multiple generations recapitulates the important role of DNMT3L in intergenerational epigenetic inheritance in mammals.
DNMT3L是哺乳动物中一种重要的表观遗传调节因子，整合基于DNA甲基化和组蛋白修饰的表观遗传回路。在此我们表明，DNMT3L是使表观遗传修饰能够代代相传的机制的一部分。在缺乏DNMT3L及其正常相互作用伙伴DNMT3A和DNMT3B的果蝇中异位表达DNMT3L，会导致逐渐且渐进的核重编程，产生黑色素瘤，且只有当这些果蝇维持五代时才会观察到这种情况。这种全局基因表达失调伴随着H3K4me3和H3K36me3水平在全局以及特定基因启动子处的异常。这些表观遗传异常（表观突变）的水平在连续几代中也逐渐增加。跨多代的表观突变的积累和遗传概括了DNMT3L在哺乳动物代际表观遗传遗传中的重要作用。
