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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 talk 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 with examples of applying this strategy to: 1) human and mouse lymphocyte development and function and 2) inference from single-cell and spacial transcriptomics aimed at healthy and diseased brain and spinal tissues.