Pervasive <i>cis</i> -regulatory co-option of a transposable element family reinforces cell identity across the mouse immune system

Transposable elements (TEs) make up about half of the human and mouse genomes and play important regulatory roles in immune responses. However, the <i>cis</i>-regulatory contribution of TEs to immune cell development is less characterized. Here, we analyzed hundreds of chromatin accessibility, gene expression, transcription factor occupancy and DNA-DNA contact datasets in diverse mouse and human immune cells. We identified two rodent-specific TE subfamilies, ORR1E and ORR1D2 (collectively, ODE) that have transformed into cell type-specific enhancers across the mouse immune system. ODE loci acquired mutations post-insertion that enable differential binding of lineage-specifying transcription factors. ODEs show evidence of evolutionary sequence constraint and contact promoters of hundreds of genes in immune cells. ODE-targeted genes show cell type-specific and mouse-specific increases in expression compared to concordant human cell types. Thus, a single TE family can undergo functionalization after its genomic spread to generate batteries of cell-specific enhancers supporting a complex developmental cascade.