Author:
Aragón Eric,Wang Qiong,Zou Yilong,Morgani Sophie M.,Ruiz Lidia,Kaczmarska Zuzanna,Su Jie,Torner Carles,Tian Lin,Hu Jing,Shu Weiping,Agrawal Saloni,Gomes Tiago,Márquez José A.,Hadjantonakis Anna-Katerina,Macias Maria J.,Massagué Joan
Abstract
TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-β signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors. FOXH1 is prebound to target sites in these loci and recruits SMAD3 independently of TGF-β signals, whereas SMAD2 remains predominantly cytoplasmic in the basal state and set to bind SMAD4 and join SMAD3:FOXH1 at target promoters in response to Nodal TGF-β signals. The results support a model in which signal-independent binding of SMAD3 and FOXH1 prime mesendoderm differentiation gene promoters for activation, and signal-driven SMAD2:SMAD4 binds to promoters that are preloaded with SMAD3:FOXH1 to activate transcription.
Funder
NIH
Spanish MINECO
IRB Barcelona
BBVA Foundation
National Natural Science Foundation of China
EMBL
NYSTEM
Postdoctoral Fellowship
Wellcome Trust
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
60 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献