103 / 2024-10-25 15:42:45

Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans

Three-dimensional genome,Chromatin interaction,Genetic variation,Transcriptional regulation

Chromatin topology profoundly impacts gene regulation, yet understanding how evolutionary divergence in chromatin topology shapes gene regulatory landscapes for distinctive human traits remains elusive. CCCTC-binding factor (CTCF) sites, acting as inherited structural codes, determine chromatin topology by forming domains and loops. Here, we reveal evolutionary divergence in CTCF-mediated chromatin topology at the domain and loop scales during primate evolution, elucidating distinct mechanisms for shaping regulatory landscapes. Human-specific divergent domains lead to a broad rewiring of transcriptional landscapes. Divergent CTCF loops synergize with species-specific enhancer activity, influencing enhancer connectivity to target genes in a synergistic yet constrained manner. Under this concordant mechanism, we reveal the novel role of human-specific CTCF loops in shaping transcriptional isoform diversity, with functional implications for disease susceptibility. Furthermore, we validate the function of these human-specific CTCF loops using human forebrain organoids. This study advances our understanding of genetic evolution from the perspective of genome architecture.