Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation

作者：Rhee Catherine; Lee Bum Kyu; Beck Samuel; Anjum Azeen; Cook Kendra R; Popowski Melissa; Tucker Haley O; Kim Jonghwan^*

来源：Genes & Development, 2014, 28(20): 2219-2232.

DOI：10.1101/gad.247163.114

• Arid3a
• trophoblast stem cells
• embryonic stem cells
• trophectoderm
• first cell fate decision
• trans-differentiation

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 Arid 3a 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 Arid 3a as a critical regulator of TE and placental development through execution of the commitment and differentiation phases of the first cell fate decision.

• 出版日期2014-10-15