DIRECTEUR: transcriptome-based prediction of small molecules that replace transcription factors for direct cell conversion

TL;DR

This paper introduces DIRECTEUR, a computational method that predicts small molecules to replace transcription factors for direct cell conversion, offering a safer alternative for regenerative medicine.

Contribution

The novel in silico method DIRECTEUR predicts small molecules that mimic transcription factors for direct cell reprogramming.

Findings

DIRECTEUR successfully predicted small molecule combinations that convert fibroblasts into neurons or cardiomyocytes.

The predicted molecules were experimentally verified and functionally related to the target conversions.

The method is expected to be useful for practical applications in regenerative medicine.

Abstract

Direct reprogramming (DR) is a process that directly converts somatic cells to target cells. Although DR via small molecules is safer than using transcription factors (TFs) in terms of avoidance of tumorigenic risk, the determination of DR-inducing small molecules is challenging.

Here we present a novel in silico method, DIRECTEUR, to predict small molecules that replace TFs for DR. We extracted DR-characteristic genes using transcriptome profiles of cells in which DR was induced by TFs, and performed a variant of simulated annealing to explore small molecule combinations with similar gene expression patterns with DR-inducing TFs. We applied DIRECTEUR to predicting combinations of small molecules that convert fibroblasts into neurons or cardiomyocytes, and were able to reproduce experimentally verified and functionally related molecules inducing the corresponding conversions. The proposed method is expected to be useful for practical applications in regenerative medicine.

The code and data are available at the following link: https://github.com/HamanoLaboratory/DIRECTEUR.git.

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