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. Overall design: 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