Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis

Luis Luna-Zurita, Christian U. Stirnimann, Sebastian Glatt, Bogac L. Kaynak, Sean Thomas, Florence Baudin, Md Abul Hassan Samee, Daniel He, Eric M. Small, Maria Mileikovsky, Andras Nagy, Alisha K. Holloway, Katherine S. Pollard, Christoph W. Müller, Benoit G. Bruneau

Research output: Contribution to journalArticleResearchpeer-review

92 Citations (Scopus)

Abstract

Summary Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been proposed as a mechanism for human congenital heart defects. We report extensive and complex interdependent genomic occupancy of TBX5, NKX2-5, and the zinc finger TF GATA4 coordinately controlling cardiac gene expression, differentiation, and morphogenesis. Interdependent binding serves not only to co-regulate gene expression but also to prevent TFs from distributing to ectopic loci and activate lineage-inappropriate genes. We define preferential motif arrangements for TBX5 and NKX2-5 cooperative binding sites, supported at the atomic level by their co-crystal structure bound to DNA, revealing a direct interaction between the two factors and induced DNA bending. Complex interdependent binding mechanisms reveal tightly regulated TF genomic distribution and define a combinatorial logic for heterotypic TF regulation of differentiation.

Original languageEnglish
Pages (from-to)999-1014
Number of pages16
JournalCell
Volume164
Issue number5
DOIs
Publication statusPublished - 25 Feb 2016
Externally publishedYes

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