Ctcf haploinsufficiency mediates intron retention in a tissue-specific manner

RNA Biol. 2021 Jan;18(1):93-103. doi: 10.1080/15476286.2020.1796052. Epub 2020 Aug 20.

Abstract

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 of Ctcf dosage on AS has not been investigated. We examined the effect of Ctcf haploinsufficiency on gene expression and AS in five tissues from Ctcf hemizygous (Ctcf+/-) mice. Reduced Ctcf levels caused distinct tissue-specific differences in gene expression and AS in all tissues. An increase in intron retention (IR) was observed in Ctcf+/- 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 of CTCF haploinsufficiency on organ transcriptomes and the role of CTCF in AS regulation.

Keywords: Alternative splicing; CTCF; exon skipping; gene expression; haploinsufficiency; intron retention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Binding Sites
  • CCCTC-Binding Factor / genetics*
  • CCCTC-Binding Factor / metabolism
  • Gene Expression Regulation*
  • Genotype
  • Haploinsufficiency*
  • Introns*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Organ Specificity
  • Protein Binding
  • Transcriptome

Substances

  • CCCTC-Binding Factor
  • Ctcf protein, mouse

Grants and funding

This work was supported by the National Health and Medical Research Council (Investigator Grant #1177305 and Project grants #1128748 and #1128175 to J.E.J.R.), Cure the Future and an anonymous foundation. Financial support was also provided by Tour de Cure (Scott Canner Research Fellowship) to C.G.B. and for research grants to C.G.B. and J.E.J.R; Tour de Rocks project support to C.G.B.; Cancer Council NSW project grants (RG11-12, RG14-09) to J.E.J.R. and C.G.B, (RG20-12 to U.S. and C.G.B.). A.B.A. is supported by a PhD Scholarship from Umm Al-Qura University in Saudi Arabia. U.S. and J.J.L.W. hold Fellowships from the Cancer Institute of New South Wales.