Cell reprogramming design by transfer learning of functional transcriptional networks.

ABSTRACT

Recent developments in synthetic biology, next-generation sequencing, and machine learning provide an unprecedented opportunity to rationally design new disease treatments based on measured responses to gene perturbations and drugs to reprogram cell behavior. The main challenges to seizing this opportunity are the incomplete knowledge of the cellular network and the combinatorial explosion of possible interventions, both of which are insurmountable by experiments. To address these challenges, we develop a transfer learning approach to control cell behavior that is pre-trained on transcriptomic data associated with human cell fates to generate a model of the functional network dynamics that can be transferred to specific reprogramming goals. The approach additively combines transcriptional responses to gene perturbations (single-gene knockdowns and overexpressions) to minimize the transcriptional difference between a given pair of initial and target states. We demonstrate the flexibility of our approach by applying it to a microarray dataset comprising over 9,000 microarrays across 54 cell types and 227 unique perturbations, and an RNASeq dataset consisting of over 10,000 sequencing runs across 36 cell types and 138 perturbations. Our approach reproduces known reprogramming protocols with an average AUROC of 0.91 while innovating over existing methods by pre-training an adaptable model that can be tailored to specific reprogramming transitions. We show that the number of gene perturbations required to steer from one fate to another increases as the developmental relatedness decreases. We also show that fewer genes are needed to progress along developmental paths than to regress. Together, these findings establish a proof-of-concept for our approach to computationally design control strategies and demonstrate their ability to provide insights into the dynamics of gene regulatory networks.