Refate identifies chemical compounds to target trans-regulatory networks for cellular conversion

Xiao, D.; Sahadevan, S.; Mangala, M. M.; Kim, H. J.; Fredericks, A.; Huang, H.; Jothi, R.; Tam, P.; Gonzalez-Cordero, A.; Zyner, K. G.; Yang, P.

doi:10.1101/2025.07.09.664003

bioRxiv · 10.1101/2025.07.09.664003

Refate identifies chemical compounds to target trans-regulatory networks for cellular conversion

Xiao, D.·Sahadevan, S.·Mangala, M. M.·Kim, H. J.·Fredericks, A.·Huang, H.·Jothi, R.·Tam, P.·Gonzalez-Cordero, A.·Zyner, K. G.·Yang, P.

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Abstract

Identifying chemical compounds that target trans-regulatory networks (TRNs) underlying molecular programs of cells for directed cellular conversion (i.e. differentiation, reprogramming, transdifferentiation, and dedifferentiation) is a key step towards advancing regenerative medicine. Recent innovations in single-cell omics technologies enabled high-resolution profiling of TRNs that govern cell identity and cell-fate decisions. Here, we introduce Refate, a computational framework that integrates large-scale multimodal single-cell atlas data to quantify cell propensity of genes, together with six drug databases, to identify chemical compounds that target TRNs for directed cellular conversion. The reconstructed TRNs, including protein-protein interactions and gene regulatory networks, alongside chemical compounds that drive the cellular conversion provide greater biological interpretability and improve efficiency and efficacy. We evaluated Refate by testing its ability to uncover known transcription factors and chemical compounds validated in experimental conversions of various cell types. Furthermore, we experimentally validated the attribute of several novel chemical compounds identified by Refate for enhancing the conversion of human embryonic stem cells to human cranial neural crest cells. Together, these findings demonstrate Refate as an effective tool for discovering chemical compounds that target TRNs to enable cellular conversion, advancing efforts towards regenerative medicine. HighlightsO_LIRefate quantifies genes for cellular conversion using multimodal single-cell atlases C_LIO_LIRefate uncovers trans-regulatory networks (TRNs) underlying cellular conversion C_LIO_LIRefate identifies chemical compounds that target TRNs for cellular conversion C_LIO_LIValidation of Refate identified chemical compounds for hESC to hCNCC conversion C_LI

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Xiao, D., Sahadevan, S., Mangala, M. M., Kim, H. J., Fredericks, A., Huang, H., Jothi, R., Tam, P., Gonzalez-Cordero, A., Zyner, K. G., Yang, P.. 2025-07-12. Refate identifies chemical compounds to target trans-regulatory networks for cellular conversion. https://doi.org/10.1101/2025.07.09.664003

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