Multiomic analyses on the contribution of transposable elements to the cis-regulatory landscape of different types of immune cells

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BACKGROUND: Transposable elements (TEs) are mobile DNA elements abundant in eukaryote genomes. While recognized as key contributors to cis-regulatory elements (CREs), their association with the cell-specific regulatory landscape of various immune cells remain largely unclear. This study aims at depicting the association of TEs with the CREs in diverse types of human immune cells in peripheral blood, with special focus on monocytes which are crucial for innate immunity. RESULTS: Using single-cell multiomic data of human peripheral blood mononuclear cells (PBMCs), we annotated the cell-specific CREs (csCREs) for different immune cell types, including sub-populations of B/T lymphocytes, monocytes, natural killer cells, and dendritic cells. A total of 63 TE families are significantly overrepresented in the annotated csCREs, including 32 primate-specific families belonging to endogenous retroviruses (ERVs). We observed a highly cell-specific TE enrichment profile in the csCREs of different immune cell types, with monocytes exhibiting the highest degree of TE enrichment. Focusing on monocytes, we found over 30% of their epigenetically-annotated enhancers are TE-derived and frequently bound by key myeloid regulators such as PU.1, ATF4 and CEBP proteins. Knockdown of SPI1 (the gene encoding PU.1) impaired the expression of hundreds of immune-related genes, including many associated with TE-derived enhancers. Interspecies comparison further showed that nearly half of human- and mouse-specific monocyte enhancers are created by TE insertions, and TE-derived enhancers correlate with the altered gene expression across species. By using luciferase reporter assay, we further validated the enhancer activity of the ERV elements adjacent to SDSL and TPK1, which are highly expressed in human relative to mouse monocytes. CONCLUSIONS: Here, we characterized the highly cell-specific profile of TE-derived CREs in different types of human blood immune cells. Integrative analysis further demonstrates the frequent contribution of TEs in creating monocyte enhancers including those specific for human or mouse, and indicates the potential involvement of TEs in mediating species-specific monocyte gene expression.

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