Group Leader University of Sydney, Children's Medical Research Institute sydney, New South Wales, Australia
Abstract: The identification of chemical compounds to target trans-regulatory networks (TRNs) that cut across molecular and cellular programs for directed cellular conversion is a crucial step towards regenerative medicine. Recent advances in single-cell resolution multi-omics technologies provide a new opportunity for capturing the complexity and cell-type-specificity of TRNs for controlling cell identity and cell-fate decisions. Here, we introduce Refate, a computational framework that integrates large-scale multimodal single-cell atlas data from humans and mice and a repertoire of six drug databases for identifying genes with high cell propensity and subsequently predicting chemical compounds that target TRNs for converting cells from a starting type to a target type with minimum input from users. The multilayered prediction of TRNs, comprised of protein complexes and gene regulatory networks, and chemical compounds that drive the cellular conversion by Refate increases biological interpretability and enhances efficacy. We evaluated Refate on its ability to uncover previously known TFs and chemical compounds that drive experimentally validated cellular conversions of various cell types. This demonstrates the potential of Refate as a valuable tool for identifying chemical compounds to target TRNs for cellular conversion.
Funding Source: National Health and Medical Research Council Investigator grant (1173469)
