[HTML][HTML] Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors

P Martin-Malpartida, M Batet, Z Kaczmarska… - Nature …, 2017 - nature.com
P Martin-Malpartida, M Batet, Z Kaczmarska, R Freier, T Gomes, E Aragón, Y Zou, Q Wang…
Nature communications, 2017nature.com
Smad transcription factors activated by TGF-β or by BMP receptors form trimeric complexes
with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been
considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been
thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation
analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-
regulatory elements. Here, we present the structural basis for specific binding of Smad3 and …
Abstract
Smad transcription factors activated by TGF-β or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene. The structures revealed a 5-bp consensus sequence GGC(GC)|(CG) as the binding site for both TGF-β and BMP-activated Smads and for Smad4. These 5GC motifs are highly represented as clusters in Smad-bound regions genome-wide. Our results provide a basis for understanding the functional adaptability of Smads in different cellular contexts, and their dependence on lineage-determining transcription factors to target specific genes in TGF-β and BMP pathways.
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