Embryonic stem (ES) cells are under precise control of both intrinsic self-renewal gene regulatory network and extrinsicgrowth factor-triggered signaling cascades. How external signaling pathways connect to core self-renewal transcriptionalcircuits is largely unknown. To probe this, we chose BMP signaling, which is previously recognized as a master control forboth self-renewal and lineage commitment of murine ES cells. Here, we mapped target gene promoter occupancy ofSMAD1/5 and SMAD4 on a genome-wide scale and found that they associate with a large group of developmentalregulators that are enriched for H3K27 trimethylation and H3K4 trimethylation bivalent marks and are repressed in theself-renewing state, whereas they are rapidly induced upon differentiation. Smad knockdown experiments further indicatethat SMAD-mediated BMP signaling is largely required for differentiation-related processes rather than directly influencingself-renewal. Among the SMAD-associated genes, we further identified Dpysl2 (previously known as Crmp2) and theH3K27 demethylase Kdm6b (previously known as Jmjd3) as BMP4-modulated early neural differentiation regulators.Combined with computational analysis, our results suggest that SMAD-mediated BMP signaling balances self-renewalversus differentiation by modulating a set of developmental regulators.

Fei T, Xia K, Li Z,Zhou B, Zhu S, Chen H, Zhang J, Chen Z, Xiao H, Han J, Chen YG. Genome-wide Mapping of SMAD Target Genes Reveals the Role of BMP Signaling in Embryonic Stem Cell Fate Determination. Genome Research . 2010, 20, 36-44.