The genetic and epigenetic determinants of enhancer-promoter contacts in mammalian evolution

Gene regulation is fundamental to biological diversity, driving differences between cell types within an organism and contributing to variation between species. DNA regions known as enhancers play a critical role in this process. Enhancers can be located millions of base pairs away from the genes they regulate, interacting with the promoters of these genes through 3D contacts within the nucleus. How enhancers find their target genes remains largely elusive. Evolution offers a unique “natural perturbation experiment” to study the principles of enhancer-promoter communication. Enhancers, and especially the sequences spanning enhancer-promoter contacts, evolve faster than the gene expression patterns they control. This raises important questions about the genetic and epigenetic factors that sustain and drive the evolution of long-range gene regulation. To address these questions, my computational project will leverage an unpublished, high-resolution dataset on enhancer-promoter contacts from five mammalian species and three tissues, along with corresponding genomic sequences, enhancer annotations, and gene expression data. My analyses will: (1) map how enhancer-promoter contacts co-evolve with genomic sequences, chromatin states, and gene expression, (2) establish how large-scale genomic rearrangements disrupt or constrain these contacts, and (3) develop and train deep learning models to predict DNA sequences underpinning the evolution of enhancer-promoter contacts. By integrating functional genomics, evolutionary biology, and machine learning, this project will uncover the mechanisms behind the evolution of long-range gene regulation, with broad implications for understanding non-coding genetic variation in evolution, disease, and synthetic biology. The fellowship will enhance my expertise in comparative genomics, 3D chromatin biology, and deep learning, while fostering new collaborations and bringing evolutionary insights to the host lab.