西亚试剂：Genome-wide mapping of SMAD target genes reveals the role o

Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination

Teng Fei1,4, Kai Xia2,4, Zhongwei Li1,5, Bing Zhou2,5, Shanshan Zhu2,5, Hua Chen1, Jianping Zhang1, Zhang Chen2, Huasheng Xiao3, Jing-Dong J. Han2,6 and Ye-Guang Chen1,6

1The State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China;
2CAS Key Laboratory of Molecular Developmental Biology and Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
3National Engineering Center for Biochip at Shanghai, Zhangjiang Hi-Tech Park, Shanghai 201203, China

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.

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