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

Despite the fundamental roles to cell fates determination in all metazoans, the mechanism by which the TGF-β family signaling is interpreted into spatial and temporal manner and multiple cell fates is still elusive. The cell context dependent function of TGF-β 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-β family signaling. HMCES-ChIP-seq using GFP-trap experiments profiling HMCES and SMAD2 chromatin association in HMCES-GFP mESCs. And SMAD2-ChIP-seq using cut&tag method experiments profiling SMAD2 chromatin association in HMCES-KO or control mESCs