Biophysically motivated regulatory network inference: progress and prospects

Abstract

Via a confluence of genomic technology and computational developments the possibility of network inference methods that automatically learn large comprehensive models of cellular regulation is closer than ever. This perspective will focus on enumerating the elements of computational strategies that, when coupled to appropriate experimental designs, can lead to accurate large-scale models of chromatin-state and transcriptional regulatory structure and dynamics. We highlight four research questions that require further investigation in order to make progress in network inference: using overall constraints on network structure like sparsity, use of informative priors and data integration to constrain individual model parameters, estimation of latent regulatory factor activity under varying cell conditions, and new methods for learning and modeling regulatory factor interactions. We conclude that methods combining advances in these four categories of required effort with new genomic technologies will result in biophysically motivated dynamic genome-wide regulatory network models for several of the best studied organisms and cell types.