Regulatory logic, thresholds and epigenetic memory:  how cis-regulatory landscapes tune gene activity during mammalian development
Development of multicellular organisms relies on differential gene activation in a single genome. In response to multiple quantitative signals, cell-type specific transcriptional programs are established that determine cell identify. Their perturbation can result in pathologies such as cancer. Large cis-regulatory landscapes integrate information on cell state, space and time to precisely tune the activity of developmental genes. How cis-regulatory landscapes decode multiple quantitative signals remains poorly understood. CisTune aims at gaining a functional and mechanistic understanding of how regulator levels are sensed, how the input from multiple regulators is integrated and how information is processed by cis-regulatory landscapes.
CisTune will use the Xist locus as a model, which controls X-chromosome inactivation, an essential developmental process in mammals. Xist's cis-regulatory landscape integrates multiple quantitative input signals that transmit information on sex and developmental time, to ensure up-regulation from one X chromosome in each female cell. In CisTune we will thus study an essential process in great depth to identify regulatory principles that control activity of the mammalian genome during development.
CisTune will use an interdisciplinary approach at the intersection of systems biology, epigenetics and gene regulation, where highly multiplexed perturbation experiments of endogenous genes are interpreted with the help of mathematical models. We will build on recent technological breakthroughs, including single-cell genomics and high-throughput CRISPR screens, which we will complement with a new approach to functionally link sequence elements to their input signals. CisTune has the potential to overcome challenges that have prevented mammalian quantitative biology of gene regulation to becoming more broadly applied and will set the stage for investigating gene regulation across multiple layers of complexity.