Cis-regulatory co-option of a transposon family reinforces cell identity across the immune system

Abstract Transposable elements (TEs) comprise about half of the human and mouse genomes and contribute to gene regulation during immune responses. However, how TEs acquire cis-regulatory functions during immune cell development remains poorly understood. Here, we analyzed hundreds of datasets profiling chromatin accessibility, gene expression, transcription factor occupancy and DNA-DNA contact across diverse mouse and human immune cell types. We identified two rodent-specific TE subfamilies, ORR1E and ORR1D2 (collectively, ODE) that have diversified after genomic insertion into cell type-specific enhancers across the mouse immune system. Post-insertion mutations in ODE loci generated differential binding sites for lineage-specifying transcription factors. ODEs showed evidence of evolutionary sequence constraint and contacted promoters of hundreds of genes in immune cells. Predicted ODE target genes were enriched for cell type-specific functions and showed increased expression in mouse compared to human cell types lacking ODEs. Together, these findings show how a single TE family can diversify after genomic spread to generate cell type-specific enhancers that reinforce lineage-specific gene programs.