HEB and E2A function as SMAD/FOXH1 cofactors

Abstract

Nodal signaling, mediated through SMAD transcription factors, is necessary for pluripotency maintenance and endoderm commitment. We identified a new motif, termed SMAD complex-associated (SCA), that is bound by SMAD2/3/4 and FOXH1 in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that two basic helix-loop-helix (bHLH) proteins-HEB and E2A-bind the SCA motif at regions overlapping SMAD2/3 and FOXH1. Furthermore, we show that HEB and E2A associate with SMAD2/3 and FOXH1, suggesting they form a complex at critical target regions. This association is biologically important, as E2A is critical for mesendoderm specification, gastrulation, and Nodal signal transduction in Xenopus tropicalis embryos. Taken together, E proteins are novel Nodal signaling cofactors that associate with SMAD2/3 and FOXH1 and are necessary for mesendoderm differentiation.

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…Furthermore, defects in the migration of NC cells upon overexpression of Tcf3∆C-GR inhibitor construct in later stages could be linked not only with NC migration, but also with formation of Twistpositive NC derivatives since its expression (Yoon et al, 2011) together with others Tcf's including; Tcf1 (Roël et al, 2003. ), Tcf12 (Yoon et al, 2011) and Tcf21 (Simrick et al, 2005) have been shown in the branchial arches at late talibud stages.…”

Id genes are essential for early heart formation

“…Consistent with our hypothesis, siRNA-mediated knockdown of two transcription factors, Tcf3 and Foxa2, is sufficient to up-regulate Mesp1 expression and promote Kdr + mesoderm formation. Mechanistically, Tcf3 is a wellcharacterized target of Id proteins (for review, see Yang et al 2014) and is also known to interact with the Smad/ Foxh1 complex to regulate Smad2/3-dependent transcription in mesendoderm progenitors (Yoon et al 2011;Wills and Baker 2015). In turn, the potent endoderm determinant Foxa2 (Stainier 2002;Viotti et al 2014), is expressed in mesendoderm progenitors in a Smad2-dependent manner in mouse embryos (Vincent et al 2003), suggesting that Tcf3 might cooperate with Smad2 to regulate Foxa2.…”

Transcriptional Control by the SMADs

“…This is a mechanism whereby activated SMAD complexes induce expression of a transcriptional regulator that subsequently interacts with the SMAD complexes at the enhancers of The first SMAD-interacting transcription factor identified was Xenopus Foxh1 (originally called FAST-1), which was shown to be absolutely required in Xenopus embryos for recruitment of an activated Smad2 -Smad4 complex to an activin-responsive element in the Xenopus mix.2 gene (Chen et al 1996(Chen et al , 1997. Binding sites for Foxh1 -Smad complexes have subsequently been found in numerous mouse genes during embryonic development and in NODAL-responsive genes in human and fish (Silvestri et al 2008;Yoon et al 2011;Lenhart et al 2013). The concept that different SMAD-interacting transcription factors could dictate the cell-type specificity of signals from TGF-b family ligands then emerged when members of the AP1 family of transcription factors (FOS and JUN) were shown to cooperate with SMAD3 -SMAD4 complexes to activate transcription from 12-O-tetradecanoyl-13-acetate (TPA)-responsive gene promoter elements (TREs) Zhang et al 1998).…”