Loss of Fam60a, a Sin3a subunit, results in embryonic lethality and is associated with aberrant methylation at a subset of gene promoters.
Loss of Fam60a, a Sin3a subunit, results in embryonic lethality and is associated with aberrant methylation at a subset of gene promoters.
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DOI：
10.7554/elife.36435
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发表时间：
2018-08-02
期刊：
影响因子：
7.7
通讯作者：
Hamada H
中科院分区：
文献类型：
--
作者：
Nabeshima R;Nishimura O;Maeda T;Shimizu N;Ide T;Yashiro K;Sakai Y;Meno C;Kadota M;Shiratori H;Kuraku S;Hamada H
我们研究了Fam 60 a在小鼠发育中的作用，Fam 60 a是一种在胚胎干细胞中高度表达的基因。Fam 60 a与Sin 3a-Hdac转录辅抑制因子复合物的组分相互作用，大多数Fam 60 a-/-胚胎表现出内脏器官发育不全并在子宫内死亡。Fam 60 a被募集到一个基因子集的启动子区，这些基因的表达在Fam 60 a-/-胚胎中被上调或下调。在Fam 60 a-/-胚胎中，Fam 60 a靶基因Adhfe 1的DNA甲基化水平在胚胎日龄（E）7.5时保持不变，但在E9.5时显著降低，表明突变体中DNA去甲基化增强。全基因组DNA甲基化检查确定了Fam 60 a-/-胚胎中几个差异甲基化区域，这些区域优先低甲基化。我们的数据表明，Fam 60 a是必要的适当的胚胎发生，至少部分是由于其在特定的基因启动子的DNA甲基化的调节。随着胚胎的发育，它的细胞继续分裂，并从非特化的胚胎干细胞转化为形成成人身体组织和器官的特化细胞。这个复杂的过程是由基因网络控制的。虽然大多数成年细胞携带相同的基因，但不同的细胞类型各自激活特定的基因组，最终赋予它们独特的特性。同样，发育中的细胞也有独特的基因表达模式，指导细胞的发育，行为及其与邻近细胞的相互作用。例如，基因Fam 60 a在胚胎干细胞中高度活跃，但直到现在，人们还不知道这个基因有什么作用。为了进一步研究这一点，Nabeshima等人研究了Fam 60 a水平正常或Fam 60 a水平降低的小鼠。结果表明，在正常水平下，Fam 60 a负责肠道正常发育。然而，水平降低的小鼠的肠道生长非常缓慢。此外，Farm 60 a似乎还调节其他几个基因，它们的活性在这些小鼠中不再受到适当的控制。Nabeshima等人发现，这是因为Fam 60 a可以与负责抑制或激活基因的蛋白质复合物相互作用。通过改变这些复合物的活性，Fam 60 a可以影响许多其他基因的活性。下一步将是找出Fam 60 a如何与影响基因活性的蛋白质复合物相互作用。更好地了解基因如何促进胚胎发育可能有助于了解流产的原因并找到预防流产的方法。
We have examined the role of Fam60a, a gene highly expressed in embryonic stem cells, in mouse development. Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex, and most Fam60a–/– embryos manifest hypoplasia of visceral organs and die in utero. Fam60a is recruited to the promoter regions of a subset of genes, with the expression of these genes being either up- or down-regulated in Fam60a–/– embryos. The DNA methylation level of the Fam60a target gene Adhfe1 is maintained at embryonic day (E) 7.5 but markedly reduced at E9.5 in Fam60a–/– embryos, suggesting that DNA demethylation is enhanced in the mutant. Examination of genome-wide DNA methylation identified several differentially methylated regions, which were preferentially hypomethylated, in Fam60a–/– embryos. Our data suggest that Fam60a is required for proper embryogenesis, at least in part as a result of its regulation of DNA methylation at specific gene promoters. As an embryo develops, its cells continue to divide and transform from unspecialized embryonic stem cells into the specialized cells that form the tissues and organs of the adult body. This complex process is controlled by a network of genes. Although most adult cells carry the same genes, different cell types each activate specific sets of genes, which ultimately gives them their unique properties. Likewise, developing cells also have unique patterns of gene expression that guide the cell’s development, behavior and its interaction with neighboring cells. For example, the gene Fam60a is highly active in embryonic stem cells, but until now, it was not known what role this gene had. To investigate this further, Nabeshima et al. studied mice that either had normal levels of Fam60a or reduced levels of Fam60a. The results showed that at a normal level, Fam60a was responsible for the intestines to develop properly. The guts of mice with reduced levels, however, grew very slowly. Moreover, Farm60a appears to regulate several other genes, and their activity was no longer controlled properly in these mice. Nabeshima et al. discovered that this was because Fam60a could interact with protein complexes responsible for repressing or activating genes. By changing the activity of these complexes, Fam60a could affect the activity of many other genes. A next step will be to find out how exactly Fam60a interacts with the protein complexes that affect the activity of genes. A better knowledge of how genes contribute to the development of an embryo may help understand the causes of miscarriage and find ways to prevent it.