Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination.
Embryonic stem (ES) cells are under precise control of both intrinsic self-renewal gene regulatory network and extrinsic growth factor-triggered signaling cascades. How external signaling pathways connect to core self-renewal transcriptional circuits is largely unknown. To probe this, we chose BMP signaling, which is previously recognized as a master control for both self-renewal and lineage commitment of murine ES cells. Here, we mapped target gene promoter occupancy of SMAD1/5 and SMAD4 on a genome-wide scale and found that they associate with a large group of developmental regulators that are enriched for H3K27 trimethylation and H3K4 trimethylation bivalent marks and are repressed in the self-renewing state, whereas they are rapidly induced upon differentiation. Smad knockdown experiments further indicate that SMAD-mediated BMP signaling is largely required for differentiation-related processes rather than directly influencing self-renewal. Among the SMAD-associated genes, we further identified Dpysl2 (previously known as Crmp2) and the H3K27 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-renewal versus differentiation by modulating a set of developmental regulators.
Fei
Teng
T
The State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China.
Xia
Kai
K
Li
Zhongwei
Z
Zhou
Bing
B
Zhu
Shanshan
S
Chen
Hua
H
Zhang
Jianping
J
Chen
Zhang
Z
Xiao
Huasheng
H
Han
Jing-Dong J
JD
Chen
Ye-Guang
YG
D000818:Animals; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D051896:Smad Proteins, Receptor-Regulated; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse