Ctcfhaploinsufficiency mediates intron retention in a tissue-specific manner

CTCF is a master regulator of gene transcription and chromatin organisation with occupancy at thousands of DNA target sites genome-wide. While CTCF is essential for cell survival, CTCF haploinsufficiency is associated with tumour development and hypermethylation. Increasing evidence demonstrates CTCF as a key player in several mechanisms regulating alternative splicing (AS), however, the genome-wide impact ofCtcfdosage on AS has not been investigated. We examined the effect ofCtcfhaploinsufficiency on gene expression and AS in five tissues fromCtcfhemizygous (Ctcf(+/-)) mice. ReducedCtcflevels caused distinct tissue-specific differences in gene expression and AS in all tissues. An increase in intron retention (IR) was observed inCtcf(+/-)liver and kidney. In liver, this specifically impacted genes associated with cytoskeletal organisation, splicing and metabolism. Strikingly, most differentially retained introns were short, with a high GC content and enriched in Ctcf binding sites in their proximal upstream genomic region. This study provides new insights into the effects ofCTCFhaploinsufficiency on organ transcriptomes and the role of CTCF in AS regulation.

Automated summary

CTCF acts as a master regulator of gene transcription and chromatin organisation, with haploinsufficiency linked to tumor development and hypermethylation. Reduced levels of CTCF in different tissues led to tissue-specific differences in gene expression and alternative splicing. In liver and kidney, CTCF haploinsufficiency resulted in increased intron retention, particularly affecting genes related to cytoskeletal organization, splicing, and metabolism.