Ctcf Haploinsufficiency Mediates Intron Retention in A Tissue-specific Manner

CCCTC binding-factor (CTCF) is a master regulator of gene transcription and chromatin organization with occupancy at tens of thousands of DNA target sites genome-wide. CTCF is essential for embryonic development and somatic cell viability and has been well-characterized as a haploinsufficient tumor suppressor. Increasing evidence demonstrates CTCF as a key player in several alternative splicing (AS) regulatory mechanisms, including transcription elongation, transcriptional regulation of splicing factors, DNA methylation, histone modification and chromatin architecture. However, the genome-wide impact of Ctcf haploinsufficiency on AS has not been investigated. We performed a transcriptomic analysis on multiple tissues from a Ctcf hemizygous (Ctcf+/-) mouse model to examine the effect of Ctcf haploinsufficiency on gene expression and AS. Distinct tissue-specific differences in gene expression were observed in Ctcf+/- mice compared to wildtype mice. While exon skipping was the most abundant form of AS in all tissues, we observed a surprisingly large number of increased intron retention (IR) events in Ctcf+/- liver and kidney. Increased IR in liver affected genes involved in cytoskeletal organization, splicing- and metabolic-related processes. This study provides further evidence for Ctcf dose-dependent and tissue-specific regulation of gene expression and AS. Our data provide a strong foundation for elucidating the mechanistic role of CTCF in AS regulation and its biological consequences. Transcriptomic analyses were performed on five tissues (brain, kidney, liver, muscle and spleen) from three wild type (C57BL/6) and three Ctcf haploinsufficient (Ctcf+/-) mice