Oestrogen receptor β regulates epigenetic patterns at specific genomic loci through interaction with thymine DNA glycosylase.
Oestrogen receptor β regulates epigenetic patterns at specific genomic loci through interaction with thymine DNA glycosylase.
复制标题
雌激素受体 β 通过与胸腺嘧啶 DNA 糖基化酶相互作用调节特定基因组位点的表观遗传模式
DOI：
10.1186/s13072-016-0055-7
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发表时间：
2016
影响因子：
3.9
通讯作者：
Rüegg J
中科院分区：
文献类型：
--
作者：
Liu Y;Duong W;Krawczyk C;Bretschneider N;Borbély G;Varshney M;Zinser C;Schär P;Rüegg J
DNA甲基化是编码表观遗传信息的一种方式，在胚胎发育过程中调节基因表达起着至关重要的作用。DNA甲基化标记是由DNA甲基转移酶建立的，最近出现了一种活跃的DNA去甲基化机制，涉及到10-11转位蛋白和胸腺嘧啶DNA糖基酶(TDG)。然而，到目前为止，还不清楚这些酶是如何被招募到特定基因组座位上并调节其DNA甲基化的。许多研究表明，序列特异性转录因子参与靶向DNA甲基化和去甲基化过程。雌激素受体β(ER-β)是一种配体诱导的转录因子，可调节雌激素对雌性激素的基因表达。以前，我们发现ERβ缺乏导致两个基因启动子甲基化模式的改变，暗示ERβ参与了DNA甲基化。在这项研究中，我们开始在全基因组水平上探索这种参与，并研究这种功能的潜在机制。使用简化代表性亚硫酸盐测序，我们比较了来自野生型和ERβ基因敲除小鼠的小鼠胚胎成纤维细胞的全基因组DNA甲基化，并确定了大约8,000个差异甲基化位置(DMP)。对选定的DMPS的验证和进一步鉴定表明，甲基化的差异与最近基因表达的变化有关。此外，将ERβ重新引入敲除细胞可以逆转高甲基化并重新激活一些基因的表达。我们还表明ERβ被招募到高甲基化的DMP周围的区域。最后，我们在这里证明了ERβ与TdG相互作用，并且TdG依赖地将ERβ与高甲基化的DMP结合。我们提供的证据表明，ERβ在调节特定基因组位置的甲基化方面起作用，这可能是由于它与这些区域的TDG相互作用的结果。我们的发现暗示了ERβ在调控靶基因甲基化方面的一种新功能，而不是直接转录调控。此外，他们通过支持序列特异性转录因子可以靶向调节DNA甲基化模式的因子的概念，阐明了DNA甲基化是如何在特定基因组座位上调节的问题。这篇文章的在线版本(doi：10.1186/s13072-0160055-7)包含补充材料，授权用户可以使用。
DNA methylation is one way to encode epigenetic information and plays a crucial role in regulating gene expression during embryonic development. DNA methylation marks are established by the DNA methyltransferases and, recently, a mechanism for active DNA demethylation has emerged involving the ten-eleven translocator proteins and thymine DNA glycosylase (TDG). However, so far it is not clear how these enzymes are recruited to, and regulate DNA methylation at, specific genomic loci. A number of studies imply that sequence-specific transcription factors are involved in targeting DNA methylation and demethylation processes. Oestrogen receptor beta (ERβ) is a ligand-inducible transcription factor regulating gene expression in response to the female sex hormone oestrogen. Previously, we found that ERβ deficiency results in changes in DNA methylation patterns at two gene promoters, implicating an involvement of ERβ in DNA methylation. In this study, we set out to explore this involvement on a genome-wide level, and to investigate the underlying mechanisms of this function. Using reduced representation bisulfite sequencing, we compared genome-wide DNA methylation in mouse embryonic fibroblasts derived from wildtype and ERβ knock-out mice, and identified around 8000 differentially methylated positions (DMPs). Validation and further characterisation of selected DMPs showed that differences in methylation correlated with changes in expression of the nearest gene. Additionally, re-introduction of ERβ into the knock-out cells could reverse hypermethylation and reactivate expression of some of the genes. We also show that ERβ is recruited to regions around hypermethylated DMPs. Finally, we demonstrate here that ERβ interacts with TDG and that TDG binds ERβ-dependently to hypermethylated DMPs. We provide evidence that ERβ plays a role in regulating DNA methylation at specific genomic loci, likely as the result of its interaction with TDG at these regions. Our findings imply a novel function of ERβ, beyond direct transcriptional control, in regulating DNA methylation at target genes. Further, they shed light on the question how DNA methylation is regulated at specific genomic loci by supporting a concept in which sequence-specific transcription factors can target factors that regulate DNA methylation patterns. The online version of this article (doi:10.1186/s13072-016-0055-7) contains supplementary material, which is available to authorised users.