BET proteins are essential for the specification and maintenance of the epiblast lineage in mouse preimplantation embryos.
BET proteins are essential for the specification and maintenance of the epiblast lineage in mouse preimplantation embryos.
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DOI：
10.1186/s12915-022-01251-0
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发表时间：
2022-03-09
期刊：
影响因子：
5.4
通讯作者：
Matsuo I
中科院分区：
文献类型：
--
作者：
Tsume-Kajioka M;Kimura-Yoshida C;Mochida K;Ueda Y;Matsuo I
在哺乳动物植入前发育过程中，随着受精卵的发育和分化，三种细胞谱系变得特定：滋养外胚层 (TE)、外胚层和原始内胚层 (PrE)。通过细胞命运决定的两个步骤，16细胞卵裂球发育成TE和内细胞团（ICM），随后后者分化为多能外胚层和PrE。尽管溴结构域和额外末端结构域 (BET) 蛋白（例如 BRD4）对于通过占据增强子来维持小鼠胚胎干细胞的基因的转录激活是必需的，但它们在小鼠植入前发育中的作用尚不清楚。为了评估 BET 蛋白缺陷对细胞谱系形成的影响，我们在 JQ1 存在的情况下培养植入前胚胎，JQ1 会阻止 BET 溴结构域与乙酰化组蛋白的结合。我们发现 BET 抑制阻断了 Nanog、Otx2 和 Sox2 等基因的转录激活，这些基因对于囊胚中外胚层谱系的形成很重要。桑葚和胚泡中谱系特异性标记的表达研究表明，BET 蛋白对于外胚层谱系的规范和维持至关重要，但对于主要胚胎外 TE 和 PrE 谱系的形成是可有可无的。其他独创性通路分析和表达研究表明，转录活性形式的信号转导子和转录激活子 3 (STAT3) 表明 BET 依赖性激活与维持外胚层谱系的 STAT3 依赖性通路部分相关。为了鉴定参与外胚层谱系形成的 BET 蛋白，我们分析了 Brd4、Brd2 和双突变体缺陷的突变体胚胎。 NANOG 阳性外胚层细胞的消除仅在 Brd4/Brd2 双缺陷桑葚中明显。因此，JQ1处理的胚胎的表型不是通过Brd4或Brd2单缺陷复制的，而是仅通过Brd4/Brd2双缺陷复制的，这证明了BRD2和BRD4在外胚层谱系规范中的冗余作用。 BET 蛋白通过在小鼠植入前发育过程中激活谱系特异性核心转录因子，对于外胚层谱系的规范和维持至关重要。在 BET 蛋白中，BRD4 在外胚层谱系的规范和维持中发挥核心作用，而 BRD2 则发挥补充作用。此外，外胚层谱系的 BET 依赖性维持可能部分与 STAT3 依赖性途径相关。在线版本包含可在 10.1186/s12915-022-01251-0 获取的补充材料。
During mammalian preimplantation development, as the fertilized egg develops and differentiates, three cell lineages become specified: trophectoderm (TE), epiblast, and primitive endoderm (PrE). Through two steps of cell fate decisions, 16-cell blastomeres develop into TE and an inner cell mass (ICM), and thereafter, the latter differentiates into pluripotent epiblast and PrE. Although bromodomain and extra-terminal domain (BET) proteins, such as BRD4, are necessary for the transcriptional activation of genes involved in the maintenance of mouse embryonic stem cells by occupying their enhancers, their roles in the development of mouse preimplantation are unknown. To evaluate the effect of BET protein deficiency on cell lineage formation, we cultured preimplantation embryos in the presence of JQ1, which blocks the binding of BET bromodomains to acetylated-histones. We found BET inhibition blocked the transcriptional activation of genes, such as Nanog, Otx2, and Sox2, important for the formation of the epiblast lineage in blastocysts. Expression studies with lineage-specific markers in morulae and blastocysts revealed BET proteins were essential for the specification and maintenance of the epiblast lineage but were dispensable for the formation of primarily extraembryonic TE and PrE lineages. Additional Ingenuity Pathway Analysis and expression studies with a transcriptionally active form of signal transducer and activator of the transcription 3 (STAT3) suggested BET-dependent activation was partly associated with the STAT3-dependent pathway to maintain the epiblast lineage. To identify BET proteins involved in the formation of the epiblast lineage, we analyzed mutant embryos deficient in Brd4, Brd2, and double mutants. Abolishment of NANOG-positive epiblast cells was only evident in Brd4/Brd2 double-deficient morulae. Thus, the phenotype of JQ1-treated embryos is reproduced not by a Brd4- or Brd2-single deficiency, but only Brd4/Brd2-double deficiency, demonstrating the redundant roles of BRD2 and BRD4 in the specification of the epiblast lineage. BET proteins are essential to the specification and maintenance of the epiblast lineage by activating lineage-specific core transcription factors during mouse preimplantation development. Among BET proteins, BRD4 plays a central role and BRD2 a complementary role in the specification and maintenance of epiblast lineages. Additionally, BET-dependent maintenance of the epiblast lineage may be partly associated with the STAT3-dependent pathway. The online version contains supplementary material available at 10.1186/s12915-022-01251-0.
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DOI：
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