Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-{beta} signaling [Research Papers]

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.

Source: Genes and Development - October 31, 2019 Category: Genetics & Stem Cells Authors: Aragon, 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., Marquez, J. A., Hadjantonakis, A.-K., Macias, M. J., Massague, J. Tags: Research Papers Source Type: research