Dissecting the sharp response of a canonical developmental enhancer reveals multiple sources of cooperativity

• DOI: 10.7554/elife.41266
• Publication Date: 2019-06-21T08:00:16Z
• Authors: Jeehae Park; Javier Estrada; Gemma Johnson; Ben J Vincent; Chiara Ricci-Tam; Meghan DJ Bragdon; Yekaterina Shulgina; Anna Cha; Zeba Wunderlich; Jeremy Gunawardena; Angela H DePace
• Keywords: 0301 basic medicine; chromosomes; Biomedical and clinical sciences; Transcription, Genetic; QH301-705.5; 1.1 Normal biological development and functioning; Science; Bioinformatics and Computational Biology; 03 medical and health sciences; computational biology; Genetic; Underpinning research; Models; Genetics; Animals; Drosophila Proteins; Developmental; Biology (General); Homeodomain Proteins; D. melanogaster; Models, Genetic; Gene Expression Profiling; Q; R; Health sciences; Gene Expression Regulation, Developmental; systems biology; Biological Sciences; Chromosomes and Gene Expression; DNA-Binding Proteins; Biological sciences; Gene Expression Regulation; gene expression; Trans-Activators; Medicine; Drosophila; Biochemistry and Cell Biology; Generic health relevance; enhancer; transcription; Transcription; Biotechnology; Transcription Factors

Developmental enhancers integrate graded concentrations of transcription factors (TFs) to create sharp gene expression boundaries. Here we examine the hunchback P2 (HbP2) enhancer which drives a sharp expression pattern in the Drosophila blastoderm embryo in response to the transcriptional activator Bicoid (Bcd). We systematically interrogate cis and trans factors that influence the shape and position of expression driven by HbP2, and find that the prevailing model, based on pairwise cooperative binding of Bcd to HbP2 is not adequate. We demonstrate that other proteins, such as pioneer factors, Mediator and histone modifiers influence the shape and position of the HbP2 expression pattern. Comparing our results to theory reveals how higher-order cooperativity and energy expenditure impact boundary location and sharpness. Our results emphasize that the bacterial view of transcription regulation, where pairwise interactions between regulatory proteins dominate, must be reexamined in animals, where multiple molecular mechanisms collaborate to shape the gene regulatory function.