Gene regulatory innovations from transposable elements in mammalian cerebellum development

Abstract

Transposable elements (TEs) are hypothesized to have driven gene regulatory innovation, yet their contributions to primate brain development at the cell type level remain largely unexplored. Using single-cell multiomics data for the cerebellum from human, macaque, marmoset, and mouse, we revealed that TE contributions to different cell types are shaped by differences in evolutionary constraint across cell types, as well as the preferential co-option of certain TEs in specific cell states. Using a sequence-based deep-learning model predicting cell-type-specific chromatin accessibility, we systematically assessed the co-option potential of TEs into cerebellar gene regulatory networks, identifying seventeen TE fragments with complex regulatory sequences in their ancestral states that facilitate their co-option as cell-type-specific cis-regulatory elements. Primate-specific HERVL (human endogenous retrovirus L) is predominantly accessible in differentiating granule cells and other rhombic-lip-derived neuroblasts during hindbrain development, and contributes to species-specific gene expression patterns. Our study uncovers a pivotal role for TEs in the evolution of the cerebellum. More generally, it demonstrates how TEs can be directly co-opted into the gene regulatory networks of specific cell types and introduces a generalizable analytical framework for dissecting their contribution to mammalian regulatory evolution.