Transposable Elements Seed Transcription Factor Binding Sites to Sequence-Specific Double-Stranded DNA Binding TF...

Transposable elements (TEs) have played a pivotal role in shaping the regulatory architecture of mammalian genomes. This contribution reports multiple lines of evidence suggesting that TE have made a significant impact on brain development by providing sequences for thousands of transcription factor binding sites (TFBS). TE-encoded TFBS have scaffolded brain developmental regulatory regions (BDRRs) across mammalian evolution. TFBS density within BDRRs has markedly increased along the evolutionary trajectory from mouse to macaque to chimpanzee, reaching its highest levels in modern humans. This density increase is accompanied by the preferential selection of specific TFs that actually bind genomic regulatory sequences. Consequently, humans and chimpanzees exhibit distinct repertoires of BDRR-bound TFs, which contribute to divergent developmental trajectories across hundreds of brain regions ranging from subcortical to telencephalon structures, including the basal ganglia (12 regions), midbrain (48), thalamus & prethalamus (85), hindbrain & cerebellum (25), limbic system & amygdala (25), neurodevelopmental structures (26). Despite the diversity of sequences contributed by different TEs, they encode TFBS for a relatively small set of ~ 700 TFs that act as central nodes organizing these regulatory landscapes. This provides a unifying framework for understanding both conserved and species-specific patterns of primate brain development. It suggests that TF networks seeded by TEs are key drivers of human neurodevelopmental innovation. Differential enrichment analyses of human vis-à-vis chimpanzee BDRRs identified 25 human BDRR-bound TFs that emanate transcriptional signatures of small TF subsets with significantly increased expression in 202 neuroanatomical structures. These observations point to a regulatory paradigm that small sets of highly-expressed genes that are significantly enriched in distinct human brain regions are selected from genes encoding TFs bound to human-specific BDRRs, thus linking "neuroanatomical transcriptional signatures" of brain structures to TFs governing brain development. Together, our findings highlight TE-derived TFBS as central architects of primate brain evolution, providing both mechanistic insight and avenues for future discovery.