Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation.
Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation.
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DOI：
10.1101/gad.247163.114
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发表时间：
2014-10-15
影响因子：
10.5
通讯作者：
Kim J
中科院分区：
文献类型：
--
作者：
Rhee C;Lee BK;Beck S;Anjum A;Cook KR;Popowski M;Tucker HO;Kim J
Rhee等人表明，Arid 3a的上调和核进入驱动胚胎干细胞中的滋养外胚层（TE）样转录程序，并维持滋养层干细胞的自我更新。Arid 3a直接激活TE特异性和滋养层谱系特异性基因，同时通过表观遗传乙酰化或脱乙酰化的差异调节直接抑制多能性基因。尽管它们起源于内细胞团，但胚胎干（ES）细胞通过ES细胞主调节因子Oct 4的抑制或TE主调节因子Caudal型同源框2（Cdx 2）的激活而经历向滋养外胚层（TE）谱系的分化。与ES细胞自我更新和多能性的深入研究相反，已经确定了很少的TE特异性调节剂，从而限制了我们对第一个细胞命运决定的机制的理解。在这里，我们表明，上调和核进入AT丰富的相互作用域3a（Arid 3a）驱动TE样转录程序在ES细胞，维持滋养层干细胞（TS）的自我更新，并促进进一步滋养层分化上游和独立的Cdx 2。因此，Arid 3a −/−小鼠着床后胎盘发育严重受损，导致早期胚胎死亡。我们提供的证据表明，Arid 3a直接激活TE特异性和滋养层谱系特异性基因，同时通过表观遗传乙酰化或脱乙酰化的差异调节直接抑制多能性基因。我们的研究结果确定Arid 3a作为TE和胎盘发育的关键调节因子，通过执行第一个细胞命运决定的定型和分化阶段。
Rhee et al. show that up-regulation and nuclear entry of Arid3a drives trophectoderm (TE)-like transcriptional programs in embryonic stem cells and maintains trophoblast stem cell self-renewal. Arid3a directly activates TE-specific and trophoblast lineage-specific genes while directly repressing pluripotency genes via differential regulation of epigenetic acetylation or deacetylation. Despite their origin from the inner cell mass, embryonic stem (ES) cells undergo differentiation to the trophectoderm (TE) lineage by repression of the ES cell master regulator Oct4 or activation of the TE master regulator Caudal-type homeobox 2 (Cdx2). In contrast to the in-depth studies of ES cell self-renewal and pluripotency, few TE-specific regulators have been identified, thereby limiting our understanding of mechanisms underlying the first cell fate decision. Here we show that up-regulation and nuclear entry of AT-rich interactive domain 3a (Arid3a) drives TE-like transcriptional programs in ES cells, maintains trophoblast stem (TS) cell self-renewal, and promotes further trophoblastic differentiation both upstream and independent of Cdx2. Accordingly, Arid3a−/− mouse post-implantation placental development is severely impaired, resulting in early embryonic death. We provide evidence that Arid3a directly activates TE-specific and trophoblast lineage-specific genes while directly repressing pluripotency genes via differential regulation of epigenetic acetylation or deacetylation. Our results identify Arid3a as a critical regulator of TE and placental development through execution of the commitment and differentiation phases of the first cell fate decision.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
64.5
作者：
Niwa, H;Toyooka, T;Rossant, J
通讯作者：
Rossant, J
影响因子：
5.3
作者：
Kuckenberg, Peter;Buhl, Sandra;Schorle, Hubert
通讯作者：
Schorle, Hubert
影响因子：
10.5
作者：
Herrscher, RF;Kaplan, MH;Tucker, PW
通讯作者：
Tucker, PW