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Nat Commun. 2017 Dec 12;8(1):2070. doi: 10.1038/s41467-017-02054-6.

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

Author information

1
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028, Barcelona, Spain.
2
EMBL Grenoble, 71 Avenue des Martyrs, CS 90181, 38042, Grenoble, Cedex 9, France.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
4
Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
5
Center for the Science of Therapeutics, Broad Institute of MIT and Harvard , 415 Main St, Cambridge, MA, 02142, USA.
6
MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
7
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028, Barcelona, Spain. maria.macias@irbbarcelona.org.
8
ICREA, Passeig Lluís Companys 23, 08010, Barcelona, Spain. maria.macias@irbbarcelona.org.

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.

PMID:
29234012
PMCID:
PMC5727232
DOI:
10.1038/s41467-017-02054-6
[Indexed for MEDLINE]
Free PMC Article

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