HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (RNA-Seq)

Despite the fundamental roles to cell fates determination in all metazoans, the mechanism by which the TGF-ß family signaling is interpreted into spatial and temporal manner and multiple cell fates is still elusive. The cell context dependent function of TGF-ß signaling largely relies on the transcriptional regulation centered by SMAD proteins. Here, we discovered that the DNA-repair related protein, HMCES contributes to early development by maintaining the nodal/activin or BMP signaling related transcriptome homeostasis. HMCES is a R-SMAD proteins binding partner that co-localizes with R-SMADs at active histone marks. However, HMCES chromatin occupancy is independent of nodal/activin or BMP signaling. Mechanically, HMCES exerts its transcriptional regulation role by counteracting R-SMAD proteins association with chromatin. In Xenopus embryo, hmces-KD causes dramatic development defects with altered left-right axis asymmetry along with increasing expression of lefty1. In sum, we disclosed the novel transcriptional regulatory function of HMCES integrated in TGF-ß family signaling. Overall design: ESCs were cultured on gelatin coated plates with 15% serum ESC culture medium. mESCs in serum-culturing (no treatment), or in activin A (50 ng/ml, R&D Systems), SB431542 (10 µM), BMP4 (10ng/ml), LDN193189 (50nM) treated for 2h were harvested for RNA-seq RNA-seq profiling of ESCs, WT and HMCES-KO.