Essential roles of Hdac1 and 2 in lineage development and genome-wide DNA methylation during mouse preimplantation development
Essential roles of Hdac1 and 2 in lineage development and genome-wide DNA methylation during mouse preimplantation development
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HDAC1 和 2 在小鼠植入前发育过程中的谱系发育和全基因组 DNA 甲基化中的重要作用
DOI：
10.1080/15592294.2019.1669375
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发表时间：
2019-06
期刊：
影响因子：
3.7
通讯作者：
Zhang Kun
中科院分区：
文献类型：
--
作者：
Zhao Panpan;Wang Huanan;Wang Han;Dang Yanna;Luo Lei;Li Shuang;Shi Yan;Wang Lefeng;Wang Shaohua;Mager Jesse;Zhang Kun
表观遗传修饰，包括 DNA 甲基化和组蛋白修饰，在哺乳动物早期胚胎发育过程中的受精后被大量重新编程。不完整的表观遗传重编程是导致体细胞核移植等辅助生殖技术产生的胚胎发育不良的一个主要因素。然而，组蛋白修饰在植入前发育中的作用尚不清楚。在这里，我们发现 Hdac1 和 2（但不是单独）的共同敲低（cKD）导致桑葚胚向囊胚转变过程中的发育失败。使用小分子 Hdac1/2 特异性抑制剂 FK228 也证实了这一结果。我们观察到 cKD 胚胎中细胞增殖减少和细胞凋亡发生率增加，这可能是由 Trp53 乙酰化增加引起的。重要的是，RNA-seq 和免疫染色分析都揭示了谱系规范未能生成滋养外胚层和多能细胞。在许多基因表达变化中，Cdx2 的大幅减少可能部分归因于 cKD 胚胎中发生的异常 Hippo 途径。此外，我们观察到整体 DNA 甲基化增加，这与 DNA 甲基转移酶和 Uhrf1 的增加一致。有趣的是，Rbbp4 和 7（两者都是几个含有 Hdac1/2 表观遗传复合物的核心成分）的缺乏会导致与 cKD 胚胎相似的表型。总体而言，Hdac1 和 2 发挥着谱系规范、细胞活力和准确的全局 DNA 甲基化所需的冗余功能，每个功能都有助于保障植入前成功发育的关键发育程序。意义表观遗传修饰的实质性变化发生在植入前发育过程中，并且在重新编程不完全时可能是有害的。然而，人们对组蛋白修饰在早期发育中的作用知之甚少。 Hdac1 和 2 的共同敲低（但不是单独敲除）导致桑葚胚向囊胚转变过程中的发育停滞，同时伴随着每个胚胎细胞数量的减少和细胞凋亡发生率的增加。此外，我们观察到第一谱系规范未能生成滋养外胚层和多能细胞，这与关键谱系特异性基因的表达减少和异常的 Hippo 途径有关。此外，发现 Dnmts 和 Uhrf1 上调导致整体 DNA 甲基化增加。因此，Hdac1 和 2 在植入前发育过程中的谱系发育、细胞凋亡和全局甲基化中发挥重叠作用。
Epigenetic modifications, including DNA methylation and histone modifications, are reprogrammed considerably following fertilization during mammalian early embryonic development. Incomplete epigenetic reprogramming is a major factor leading to poor developmental outcome in embryos generated by assisted reproductive technologies, such as somatic cell nuclear transfer. However, the role of histone modifications in preimplantation development is poorly understood. Here, we show that co-knockdown (cKD) of Hdac1 and 2 (but not individually) resulted in developmental failure during the morula to blastocyst transition. This outcome was also confirmed with the use of small-molecule Hdac1/2-specific inhibitor FK228. We observed reduced cell proliferation and increased incidence of apoptosis in cKD embryos, which were likely caused by increased acetylation of Trp53. Importantly, both RNA-seq and immunostaining analysis revealed a failure of lineage specification to generate trophectoderm and pluripotent cells. Among many gene expression changes, a substantial decrease of Cdx2 may be partly accounted for by the aberrant Hippo pathway occurring in cKD embryos. In addition, we observed an increase in global DNA methylation, consistent with increased DNA methyltransferases and Uhrf1. Interestingly, deficiency of Rbbp4 and 7 (both are core components of several Hdac1/2-containing epigenetic complexes) results in similar phenotypes as those of cKD embryos. Overall, Hdac1 and 2 play redundant functions required for lineage specification, cell viability and accurate global DNA methylation, each contributing to critical developmental programs safeguarding a successful preimplantation development. Significance Substantial changes to epigenetic modifications occur during preimplantation development and can be detrimental when reprogrammed incompletely. However, little is known about the role of histone modifications in early development. Co-knockdown of Hdac1 and 2, but not individually, resulted in developmental arrest during morula to blastocyst transition, which was accompanied by reduced cell number per embryo and increased incidence of apoptosis. Additionally, we observed a failure of first lineage specification to generate trophectoderm and pluripotent cells, which were associated with reduced expression of key lineage-specific genes and aberrant Hippo pathway. Moreover, an increase in global DNA methylation was found with upregulated Dnmts and Uhrf1. Thus, Hdac1 and 2 play overlapping roles in lineage development, apoptosis, and global methylation during preimplantation development.
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DOI：
10.1073/pnas.1118403109
发表时间：
2012-02-21
影响因子：
11.1
作者：
Ma, Pengpeng;Pan, Hua;Schultz, Richard M.
通讯作者：
Schultz, Richard M.
影响因子：
56.9
作者：
Jennifer Zenker;Melanie D. White;Rachel Templin;Robert G. Parton;Oliver Thorn-Seshold;Stéphanie Bissière;N. Plachta;N. Plachta
通讯作者：
Jennifer Zenker;Melanie D. White;Rachel Templin;Robert G. Parton;Oliver Thorn-Seshold;Stéphanie Bissière;N. Plachta;N. Plachta
影响因子：
30.8
作者：
Rountree, MR;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
10.5
作者：
Yamaguchi, Teppei;Cubizolles, Fabien;Matthias, Patrick
通讯作者：
Matthias, Patrick
影响因子：
64.5
作者：
Hassig, CA;Fleischer, TC;Ayer, DE
通讯作者：
Ayer, DE