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

Pau Martin-Malpartida, Marta Batet, Zuzanna Kaczmarska, Regina Freier, Tiago Gomes, Eric Aragón, Yilong Zou, Qiong Wang, Qiaoran Xi, Lidia Ruiz, Angela Vea, José A. Márquez, Joan Massagué and Maria J. Macias ()
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Pau Martin-Malpartida: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Marta Batet: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Zuzanna Kaczmarska: EMBL Grenoble
Regina Freier: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Tiago Gomes: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Eric Aragón: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Yilong Zou: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Qiong Wang: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Qiaoran Xi: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Lidia Ruiz: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
Angela Vea: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
José A. Márquez: EMBL Grenoble
Joan Massagué: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Maria J. Macias: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02054-6

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