Gene regulatory innovations from transposable elements in primate cerebellum development.

Transposable elements are hypothesized to have driven gene regulatory innovation, yet their contributions to primate brain development at the cell type level remain underexplored. Here, we use single-cell multiomics data from human, macaque, marmoset, and mouse cerebella to show that transposable element contributions to different cell types are shaped by varying degrees of constraints across cell types, as well as the preferential co-option of certain transposable elements in specific cell states. Using a sequence-based deep-learning model that predicts cell-type-specific chromatin accessibility, we systematically assess the co-option potential of transposable elements into cerebellar gene regulatory networks, identifying twelve transposable element subfamilies with complex regulatory sequences in their ancestral states that facilitate their co-option as cell-type-specific cis-regulatory elements. Preservation of these ancestral regulatory sequences, as well as the active chromatin environment surrounding the insertion site, is the major determinant of the accessibility of extant copies. Lineage-specific accessible copies contribute to human-specific gene expression. Broadly, we demonstrate how transposable elements can be flexibly co-opted into cell-type-specific gene regulatory networks, and introduce a generalizable analytical framework for dissecting their contribution to mammalian regulatory evolution.