Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling Journal Article
| Authors: | Aragón, E.; Wang, Q.; Zou, Y.; Morgani, S. M.; Ruiz, L.; Kaczmarska, Z.; Su, J.; Torner, C.; Tian, L.; Hu, J.; Shu, W.; Agrawal, S.; Gomes, T.; Márquez, J. A.; Hadjantonakis, A. K.; Macias, M. J.; Massagué, J. |
| Article Title: | Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling |
| 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. © 2019 Aragón et al.; Published by Cold Spring Harbor Laboratory Press. |
| Keywords: | embryonic stem cell; tgf-β signaling; smad2; mesendoderm differentiation; smad3; foxh1; pioneer transcription factor; smad2 structure |
| Journal Title: | Genes and Development |
| Volume: | 33 |
| Issue: | 21-22 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2019-01-01 |
| Start Page: | 1506 |
| End Page: | 1524 |
| Language: | English |
| DOI: | 10.1101/gad.330837.119 |
| PUBMED: | 31582430 |
| PROVIDER: | scopus |
| PMCID: | PMC6824466 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 December 2019 -- Source: Scopus |
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