Repression of somatic genes by selective recruitment of HDAC3 by BLIMP1 is essential for mouse primordial germ cell fate determination
Repression of somatic genes by selective recruitment of HDAC3 by BLIMP1 is essential for mouse primordial germ cell fate determination
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BLIMP1 通过选择性招募 HDAC3 来抑制体细胞基因对于小鼠原始生殖细胞命运的决定至关重要
DOI：
10.1016/j.celrep.2018.07.108
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发表时间：
2018
期刊：
影响因子：
8.8
通讯作者：
Matsui Yasuhisa
中科院分区：
文献类型：
--
作者：
Mochizuki Kentaro;Hayashi Yohei;Sekinaka Tamotsu;Otsuka Kei;Ito-Matsuoka Yumi;Kobayashi Misato;Oki Shinya;Takehara Asuka;Kono Tomohiro;Osumi Noriko;Matsui Yasuhisa
原始生殖细胞（PGC）的命运由多能外胚层决定。参与 PGC 形成的信号通路和转录调节因子已被确定，但 PGC 命运决定的详细分子机制仍知之甚少。通过 RNAi 筛选，我们确定组蛋白脱乙酰酶 3 (HDAC3) 是 PGC 形成的调节因子。Hdac3 缺陷导致体外和体内新生 PGC 减少，并且在 PGC 诱导过程中体细胞发育基因因 Hdac3 敲低而解除抑制。我们还证明了外胚层样细胞体细胞发育基因中 HDAC3 的 BLIMP1 依赖性富集以及 H3 和 H4 组蛋白的脱乙酰化。此外，HDAC3/BLIMP1靶向的体细胞基因产物富含PGC决定基因；这些基因产物在培养的 PGC 样细胞中过度表达导致 PGC 决定基因的抑制。我们认为，BLIMP1 将 HDAC3 选择性招募到体细胞基因以及随后对这些体细胞基因的抑制对于 PGC 命运的决定至关重要。
Primordial germ cells (PGCs) are fate determined from pluripotent epiblasts. Signaling pathways and transcriptional regulators involved in PGC formation have been identified, but detailed molecular mechanisms of PGC fate determination remains poorly understood. Using RNAi screening, we identified histone deacetylase 3 (HDAC3) as a regulator of PGC formation.Hdac3deficiency resulted in decreased nascent PGCsin vitroandin vivo, and somatic developmental genes were de-repressed byHdac3knockdown during PGC induction. We also demonstrated BLIMP1-dependent enrichment of HDAC3 and deacetylation of H3 and H4 histones in the somatic developmental genes in epiblast-like cells. In addition, the HDAC3/BLIMP1-targeted somatic gene products were enriched in PGC determinant genes; overexpression of these gene products in PGC-like cells in culture resulted in repression of PGC determinant genes. We propose that selective recruitment of HDAC3 to somatic genes by BLIMP1 and subsequent repression of these somatic genes are crucial for PGC fate determination.