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

Abstract

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 selfrenewal, 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.

ARID3A is required for mammalian placenta development

“…Our initial in vitro investigation in the human model further supports a requirement for ARID3A in initiation of ES to TS-like cell conversion through modulation of underlying transcriptional programs. Taken with our previous mechanistic observations (Rhee et al, 2014), our results identify ARID3A as an indispensable component of placental commitment, hemostasis and immune tolerance.…”

“…Similar to the mouse, ARID3A levels in human are the highest in the placenta as compared to all other tissues (Li et al, 2013; Rhee et al, 2014)(Fig. 1C).…”

“…2A). Since our previous studies (Rhee et al, 2014) detected high ARID3A expression in the TE, we carefully examined the gross anatomy of all E10.5 and E11.5 surviving embryos and placentas from Arid3a mutant heterozygous crosses. Arid3a mutants exhibited a range of phenotypes, from indistinguishable, to small, to paler embryos and placentas—further indications of the vasoconstriction characterized previously (Webb et al, 2011)(Figs.…”

“…Our previous studies showed that AT-Rich Interactive Domain 3A (ARID3A) is essential for the first cell fate decision (Rhee et al, 2014). We found that overexpression (OE) of ARID3A alone is sufficient for trans-differentiation of embryonic stem (ES) cells to trophoblast stem (TS)-like cells—the in vitro counterpart of the TE layer of the blastocyst.…”

The Arid3a Transcription Factor Rescues Natural and RAS-V12-Induced Senescence Via a Rb-Dependent Pathway

“…Bdp/Arid3b was cloned as a protein that associates directly via its ARID domain with Rb (Numata et al, 1999). While E2FBP1/Dril1 is expressed broadly in human tissues, its mouse (m) ortholog, Arid3a/Bright (for B cell regulator of IgH transcription) (Herrscher et al, 1995) is expressed exclusively in developing hematopoietic lineages within the embryo and placenta (Rhee et al, 2014;, but restricted to B lymphocytes in the adult (Webb et al, 1998;Nixon et al, 2004). Arid3a, in a complex with Bruton's tyrosine kinase (btk) and TFII-I, binds to specific AT-rich motifs within the nuclear matrixattachment regions (MARs) of the IgH intronic enhancer (Eµ) resulting in an activated transcription of heavy chain µ chains (Herrscher et al, 1995;Kim and Tucker, 2006;Lin et al, 2007;Rajaiya et al, 2005;Webb et al, 1999;.…”