Padi2/3 Deficiency Alters the Epigenomic Landscape and Causes Premature Differentiation of Mouse Trophoblast Stem Cells.
Padi2/3 Deficiency Alters the Epigenomic Landscape and Causes Premature Differentiation of Mouse Trophoblast Stem Cells.
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组蛋白瓜氨酸化是一种相对较少研究的表观遗传修饰，涉及精氨酸残基不可逆转化为瓜氨酸。它是由一种被称为蛋白质精氨酸脱亚胺酶（PADIs）的小酶家族赋予的。PADI功能支持胚胎干细胞的多能状态，但在其他情况下，也促进有效的细胞分化。在目前的研究中，我们试图更深入地了解padi在小鼠滋养细胞干细胞（TSCs）中的可能作用。我们发现Padi2和Padi3是TSCs中表达最多的PADI家族成员，并在分化后迅速下调。Padi2/3双敲除（DKO） TSCs表达水平较低的干细胞转录因子CDX2和SOX2，容易分化为超大的滋养层巨细胞，这可能是中心体复制缺陷介导的。有趣的是，Padi2/3 DKO TSCs表现出表观基因组景观的改变，h3k9me3标记的色中心灶减少，整体5-甲基胞嘧啶水平降低。DNA甲基化分析表明，这种效应在关键滋养细胞基因的CpG岛（如Gata3、Peg3、Socs3和Hand1）上尤为明显。作为低甲基化状态的结果，这些因子在Padi2/3 DKO TSCs中上调，推动其过早分化。我们的数据揭示了PADI2/3通过调节DNA甲基化景观来限制早熟滋养细胞分化，在保护TSCs干细胞状态方面的关键表观遗传学作用。
Histone citrullination is a relatively poorly studied epigenetic modification that involves the irreversible conversion of arginine residues into citrulline. It is conferred by a small family of enzymes known as protein arginine deiminases (PADIs). PADI function supports the pluripotent state of embryonic stem cells, but in other contexts, also promotes efficient cellular differentiation. In the current study, we sought to gain deeper insights into the possible roles of PADIs in mouse trophoblast stem cells (TSCs). We show that Padi2 and Padi3 are the most highly expressed PADI family members in TSCs and are rapidly down-regulated upon differentiation. Padi2/3 double knockout (DKO) TSCs express lower levels of stem cell transcription factors CDX2 and SOX2 and are prone to differentiate into extremely large trophoblast giant cells, an effect that may be mediated by centrosome duplication defects. Interestingly, Padi2/3 DKO TSCs display alterations to their epigenomic landscape, with fewer H3K9me3-marked chromocentric foci and globally reduced 5-methylcytosine levels. DNA methylation profiling identifies that this effect is specifically evident at CpG islands of critical trophoblast genes, such as Gata3, Peg3, Socs3 and Hand1. As a consequence of the hypomethylated state, these factors are up-regulated in Padi2/3 DKO TSCs, driving their premature differentiation. Our data uncover a critical epigenetic role for PADI2/3 in safeguarding the stem cell state of TSCs by modulating the DNA methylation landscape to restrict precocious trophoblast differentiation.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
16.6
作者：
Latos PA;Goncalves A;Oxley D;Mohammed H;Turro E;Hemberger M
通讯作者：
Hemberger M
影响因子：
21.3
作者：
Ng, Ray Kit;Dean, Wendy;Dawson, Claire;Lucifero, Diana;Madeja, Zofia;Reik, Wolf;Hemberger, Myriam
通讯作者：
Hemberger, Myriam
影响因子：
7.7
作者：
Perez-Garcia V;Lea G;Lopez-Jimenez P;Okkenhaug H;Burton GJ;Moffett A;Turco MY;Hemberger M
通讯作者：
Hemberger M
影响因子：
9.2
作者：
Lehnertz, B;Ueda, Y;Peters, AHFM
通讯作者：
Peters, AHFM