In vivo genome-wide profiling reveals a tissue-specific role for 5-formylcytosine.
In vivo genome-wide profiling reveals a tissue-specific role for 5-formylcytosine.
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DOI：
10.1186/s13059-016-1001-5
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发表时间：
2016-06-29
期刊：
影响因子：
12.3
通讯作者：
Reik W
中科院分区：
文献类型：
--
作者：
Iurlaro M;McInroy GR;Burgess HE;Dean W;Raiber EA;Bachman M;Beraldi D;Balasubramanian S;Reik W
在 TET 和胸腺嘧啶 DNA 糖基化酶 (TDG) 存在的情况下，可以调节胞嘧啶的全基因组甲基化。 TET 能够将 5-甲基胞嘧啶 (5mC) 氧化为 5-羟甲基胞嘧啶 (5hmC)、5-甲酰胞嘧啶 (5fC) 和 5-羧基胞嘧啶 (5caC)。 TDG可以切除氧化产物5fC和5caC，启动碱基切除修复。这些修饰的碱基在基因组中是稳定的且可检测到的，这表明它们本身可能具有表观遗传功能。然而，对 5fC 全基因组分布的功能研究仅限于基于细胞培养的系统，而其体内概况仍然未知。在这里，我们描述了对野生型和 Tdg 缺陷 E11.5 小鼠胚胎的一系列组织中 5fC 的体内全基因组谱的首次分析。 TDG 耗尽后胞嘧啶甲酰化谱的变化表明 TET/TDG 介导的主动去甲基化优先发生在内含子-外显子边界，并揭示了 TDG 在塑造 CpG 岛 5fC 分布中的主要作用。此外，我们发现活性增强子区域特别表现出高水平的 5fC，从而产生特征性的组织诊断模式，这表明其在胚胎发育中的作用。 5fC 的组织特异性分布可以通过 TET 介导的氧化和 TDG 切除的共同作用来调节。胚胎发育过程中 5fC 的体内概况与胚胎干细胞相似，具有共同的关键特征，包括 5fC 在增强子和基因内区域的富集。此外，通过以组织特异性方式研究小鼠胚胎 5fC 谱，我们确定了参与组织发育的活性增强子的靶向富集。本文的在线版本 (doi:10.1186/s13059-016-1001-5) 包含补充材料，可供授权用户使用。
Genome-wide methylation of cytosine can be modulated in the presence of TET and thymine DNA glycosylase (TDG) enzymes. TET is able to oxidise 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). TDG can excise the oxidative products 5fC and 5caC, initiating base excision repair. These modified bases are stable and detectable in the genome, suggesting that they could have epigenetic functions in their own right. However, functional investigation of the genome-wide distribution of 5fC has been restricted to cell culture-based systems, while its in vivo profile remains unknown. Here, we describe the first analysis of the in vivo genome-wide profile of 5fC across a range of tissues from both wild-type and Tdg-deficient E11.5 mouse embryos. Changes in the formylation profile of cytosine upon depletion of TDG suggest TET/TDG-mediated active demethylation occurs preferentially at intron-exon boundaries and reveals a major role for TDG in shaping 5fC distribution at CpG islands. Moreover, we find that active enhancer regions specifically exhibit high levels of 5fC, resulting in characteristic tissue-diagnostic patterns, which suggest a role in embryonic development. The tissue-specific distribution of 5fC can be regulated by the collective contribution of TET-mediated oxidation and excision by TDG. The in vivo profile of 5fC during embryonic development resembles that of embryonic stem cells, sharing key features including enrichment of 5fC in enhancer and intragenic regions. Additionally, by investigating mouse embryo 5fC profiles in a tissue-specific manner, we identify targeted enrichment at active enhancers involved in tissue development. The online version of this article (doi:10.1186/s13059-016-1001-5) contains supplementary material, which is available to authorized users.