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bioRxiv · 10.64898/2025.12.22.696042

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

Chobirko, J. D.·Feschotte, C.·Grimson, A.
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Abstract

Transposable elements (TEs) make up about half of the human and mouse genomes and play important regulatory roles in immune responses. However, the cis-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.

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Chobirko, J. D., Feschotte, C., Grimson, A.. 2025-12-25. Pervasive cis-regulatory co-option of a transposable element family reinforces cell identity across the mouse immune system. https://doi.org/10.64898/2025.12.22.696042

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