Precision of collective, distributed, dynamic gene regulation – DISTANT

Summary: Quantitative elucidation of how protein expression is regulated with high precision, and how and why it can fail, is important for understanding the basic biology of organism development, as well as the genesis of many diseases. In the context of development, this precision leads to boundaries among different cell types in an embryo resolved down to the width of a single cell. Recent experiments point out the role of multiple enhancers, some of which are distant from the initiation site of transcription, opening up the question of how the information from these molecular sensors is integrated in space and time, and what are the advantages and disadvantages of such distributed sensing in gene regulation. How cells achieve the needed protein expression precision in the face of biochemical noise, what is the importance of dynamical profiles of morphogens, of multiple interacting morphogens, and of spatially distributed sensing at different genomic locations, remain open questions, which are the focus of this project. Our focus is to build theoretical and computational models to understand the physical limits that molecular architectures impose on the precision and speed of regulation.

Intellectual Merit: We will develop a predictive analytical and computational theory of the role of dynamical, spatially extended interactions among multiple enhancers, multiple transcription factors, and multiple promoters for precise gene regulation in eukaryotic development. We will use early fly development as a concrete example, motivated by large amounts of existing data and our existing relationship with experimentalists. The theory will address the role of multiple proximal and distal enhancers, characterize the effects of cross-talk among various enhancers, promoters, and TFs on precision of gene regulation, and elucidate the constraints that the dynamical nature of the development process imposes on molecular implementations of transcriptional hubs.

Broader Impact: This project will support and administer participation of U.S. based trainees at the 2021 Les Houches Summer School in Biophysics, train women and underrepresented minorities in theoretical biophysics, and endow them with the international perspective on science and society, essential in the modern world.