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Summary: Here, we present a computational pipeline to obtain quantitative models that characterize the relationship of gene expression with the epigenetic marking at enhancers or promoters in mouse embryonic stem cells. Our protocol consists of (i) generating predictive models of gene expression from epigenetic information (such as histone modification ChIP-seq) at enhancers or promoters and (ii) assessing the performance of these predictive models. This protocol could be applied to other biological scenarios or other types of epigenetic data.For complete details on the use and execution of this protocol, please refer to Gonzalez-Ramirez et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.