Beyond DNA binding: CTCF at the crossroads of chromatin architecture and epitranscriptomic regulation

Transcriptional regulation is a crucial biological process that enables accurate gene expression, allowing cells to maintain their identity and respond to environmental stimuli. CCCTC-binding factor is a fundamental protein that actively involves itself in transcriptional regulation, serving as a highly conserved architectural regulator. CTCF is traditionally acknowledged for its function in chromatin organization and insulation. It coordinates active or repressed transcription by establishing topologically associated domains and also helps in preserving enhancer-promoter identity. In addition to its DNA-binding roles, CTCF significantly participates in RNA biology. It engages with nascent RNA, pre-mRNA, and long non-coding RNAs via its RNA-binding domain, thereby affecting different transcriptional dynamics. Simultaneously, the swiftly advancing domain of epitranscriptomics has revealed other RNA modifications, such as N6-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), and pseudouridine (Ψ), which jointly regulate RNA stability, transport, translation, and destruction. Hence, the dysregulation of these changes or CTCFactivity is closely linked to oncogenesis, developmental problems, and resistance to therapy. The intersection of CTCF-mediated genomic architecture with epitranscriptomic regulation highlights its function as a complex integrator of chromatin and RNA networks. This review consolidates contemporary understanding of CTCF's twin activities in DNA and RNA binding, examining how their interaction influences transcriptional regulation, RNA processing, and disease relevance.