CTCF-Mediated Chromatin Loops between Promoter and Gene Body Regulate Alternative Splicing across Individuals
Mariana Ruiz-Velasco, Manjeet Kumar, Mang Ching Lai, Pooja Bhat, Ana Belen Solis-Pinson, Alejandro Reyes, Stefan Kleinsorg, Kyung-Min Noh, Toby J. Gibson, and Judith B. Zaugg
The CCCTC-binding factor (CTCF) is known to estab- lish long-range DNA contacts that alter the three- dimensional architecture of chromatin, but how the presence of CTCF influences nearby gene expres- sion is still poorly understood. Here, we analyze CTCF chromatin immunoprecipitation sequencing, RNA sequencing, and Hi-C data, together with genotypes from a healthy human cohort, and mea- sure statistical associations between inter-individual variability in CTCF binding and alternative exon usage. We demonstrate that CTCF-mediated chro- matin loops between promoters and intragenic re- gions are prevalent and that when exons are in phys- ical proximity with their promoters, CTCF binding correlates with exon inclusion in spliced mRNA. Genome-wide, CTCF-bound exons are enriched for genes involved in signaling and cellular stress- response pathways. Structural analysis of three spe- cific examples, checkpoint kinase 2 (CHK2), CDC- like kinase 3 (CLK3), and euchromatic histone-lysine N-methyltransferase (EHMT1), suggests that CTCF- mediated exon inclusion is likely to downregulate enzyme activity by disrupting annotated protein do- mains. In total, our study suggests that alternative exon usage is regulated by CTCF-dependent chro- matin structure.