Functionalization of transposable element-derived enhancers across mouse hematopoiesis 3835

Description Transposable elements (TEs) make up half of the human and mouse genome but remain understudied. Evidence is growing that TEs play important roles in immunity as a subset of TE enhancers regulate innate immunity genes. However, the cis-regulatory contribution of TEs across immune cell development is not well understood. Mining more than 300 chromatin accessibility datasets (ATAC-seq) across mouse hematopoietic cell lineages, we identified two subfamilies of rodent-specific retroviral LTRs, ORR1E and ORR1D2 (ODE), which are enriched in accessible chromatin across all immune cell types. Unsupervised clustering show that ∼2,900 ODEs stratify by cell type-specific accessibility. Each ODE cluster is enriched for a unique combination of sequence motifs for cell lineage-specifying TFs, such as PU.1, IRF8, and RORγ, which we validated with ChIP-seq. By correlating ODE accessibility with gene expression (RNA-seq), we predicted hundreds of ODE-gene interactions. We generated Micro-C (DNA-DNA contact) in CD8+ T cells and validated ∼120 ODE-gene interactions. Predicted target genes are more expressed in mouse than in human CD8+ T cells. Lastly, accessible ODEs have higher sequence conservation across rodents than other ODEs. Together, these data suggest that despite their common origin, ODE LTRs have subfunctionalized into cell type-specific enhancers across mouse hematopoiesis. We propose that ODE enhancers were co-opted during rodent evolution to reinforce cell type identity. Funding Sources F31AI183775 Topic Categories Computational and Systems Immunology (COMP)