Kipoi Seminar - Sagar Gosai (Broad Institute of Harvard and MIT) 

Title: Machine-guided design of synthetic cell type-specific cis-regulatory elements
Abstract:
Cis-regulatory elements (CREs) control gene expression, orchestrating tissue identity, developmental timing, and stimulus responses, which collectively define the thousands of unique cell types in the body. While there is great potential for strategically incorporating CREs in therapeutic or biotechnology applications that require tissue specificity, there is no guarantee that an optimal CRE for these intended purposes has arisen naturally. Here, we present a platform to engineer and validate synthetic CREs capable of driving gene expression with programmed cell type specificity. We leverage innovations in deep neural network modeling of CRE activity across three cell types, efficient in silico optim ization, and massively parallel reporter assays (MPRAs) to design and empirically test thousands of CREs. Through large-scale in vitro validation, we show that synthetic sequences are more effective at driving cell type-specific expression in three cell lines compared to natural sequences from the human genome, and achieve specificity in analogous tissues when tested in vivo. Synthetic sequences exhibit distinct motif vocabulary associated with activity in the on-target cell type and the simultaneous reduction of activity in off-target cells. Together, we provide a generalizable framework to prospectively engineer CREs from MPRA models and demonstrate the required literacy to write fit-for-purpose regulatory code.