Retroelements-driven regulatory evolution of human genes and molecular processes: analysis of genome binding profiles of transcription factors and histone modifications

This PhD thesis investigates the regulatory role of human retroelements (REs), such as LINEs, SINEs, and HERVs, which constitute over 40% of the genome. Using a novel computational framework named RetroSpect, the study quantifies RE-associated regulatory influence by co-mapping transcription factor binding sites (TFBS) and six histone modifications with RE coordinates and gene transcription start sites across 13 human cell lines. Findings reveal that REs provide 61.4% of uniquely mapped TFBS in promoter-proximal regions, with SINEs acting as the primary co-opted class. While core housekeeping processes like translation and ribosome biogenesis remain RE-deficient and conserved, molecular pathways involved in environmental interaction—including lipid metabolism, detoxification, and sensory perception—exhibit accelerated RE-driven evolution. Furthermore, REs are major drivers of non-coding RNA evolution and contribute to oncogenic regulatory programs, with a consensus set of 92 genes consistently activated by RE-linked promoters enriched in pathways for small cell lung cancer and chronic myeloid leukemia progression as well as viral response. The results demonstrate that REs have fundamentally remodeled the human regulome as catalysts for both evolutionary innovation and disease.