Tu Jiajie, Liao Jinyue, Luk Alfred Chun Shui, Tang Nelson Leung Sang, Chan Wai-Yee, Lee Tin-Lap
Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region, China.; Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China..
Reproduction, Development and Endocrinology Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region, China.; Shandong University (CUHK-SDU) Joint Laboratory on Reproductive Genetics, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China.
Int J Biochem Cell Biol. 2015 Oct;67:115-20. doi: 10.1016/j.biocel.2015.05.002. Epub 2015 May 12.
For decades, DNA methylation at the 5 position of cytosine (5mC) catalyzed by DNA methyltransferases (DNMTs) is a well-known epigenetic modification in mammalian genome, where it modulates chromatin remodeling and transcriptional silencing. The discovery of Ten-eleven translocation (TET) enzymes that oxidize 5mC to 5-hydroxymethylcytosine (5hmC) prompts a new era of DNA demethylation research. It is now established that in DNA demethylation pathway 5mC is first converted to 5-hydroxymethylcytosine (5hmC), then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) through TETs. Conversion to unmethylated cytosine (5C) is further facilitated by excision mechanism through thymine-DNA glycosylase (TDG) or base excision repair (BER) pathway. Our understanding of DNMTs and TETs on epigenetic dynamics of cytosine methylation has led to a completion of the methylation (Yin) - demethylation (Yang) cycle on epigenetic modifications on cytosine. However, the regulations on DNA demethylation pathway remain largely unknown. In this review, we provide the recent advances on epigenetic dynamics of DNA demethylation and its potential control from the prespective of small non-coding RNA-mediated regulation. Specifically, we will illustrate how microRNAs contribute to active DNA demethylation control in normal and disease development based on recent findings in stem cells and cancer. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.
几十年来，由DNA甲基转移酶（DNMTs）催化的胞嘧啶第5位的DNA甲基化（5mC）是哺乳动物基因组中一种广为人知的表观遗传修饰，它在其中调节染色质重塑和转录沉默。将5mC氧化为5-羟甲基胞嘧啶（5hmC）的Tet蛋白（Ten-eleven translocation）的发现开启了DNA去甲基化研究的新时代。现在已经确定，在DNA去甲基化途径中，5mC首先通过Tet蛋白转化为5-羟甲基胞嘧啶（5hmC），然后转化为5-甲酰基胞嘧啶（5fC）和5-羧基胞嘧啶（5caC）。通过胸腺嘧啶-DNA糖基化酶（TDG）的切除机制或碱基切除修复（BER）途径进一步促进了向未甲基化胞嘧啶（5C）的转化。我们对DNMTs和Tet蛋白在胞嘧啶甲基化表观遗传动力学方面的理解，导致了胞嘧啶表观遗传修饰上甲基化（阴）-去甲基化（阳）循环的完成。然而，对DNA去甲基化途径的调控仍然很大程度上未知。在这篇综述中，我们从小非编码RNA介导的调控角度提供了DNA去甲基化表观遗传动力学及其潜在调控的最新进展。具体来说，我们将根据干细胞和癌症方面的最新发现，说明微小RNA如何在正常和疾病发展中促进活性DNA去甲基化控制。本文是名为“发育和疾病中的表观遗传动力学”的定向专题的一部分。
