Ctcf Haploinsufficiency Mediates Intron Retention in A Tissue-specific Manner
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PROVIDER: PRJNA590145 | ENA |
REPOSITORIES: ENA
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Project description: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.
2020-11-11 | GSE140532 | GEO
Project description: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.
| S-EPMC7834090 | biostudies-literature
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Project description:We present an analysis of intron retention under stress from two different drugs and their combinations in yeast Saccharomyces cerevisiae. We previously established isogrowth profiling, a method to abstract the non-specific effects of growth rate inhibition from the specific effect of perturbation by a small molecule: two drugs are used at varied ratios, but at fixed overall growth inhibition. Here, cycloheximide and LiCl were used at seven different ratios along the 50% growth inhibition isobole and the total ribodepleted RNA was sequenced. This allowed us to gauge the changes in intron retention due to the used drugs, while ensuring that the effects are not caused by growth inhibition. We found a prominent increase in intron retention under LiCl treatment that preferentially affects introns contained in the transcripts of ribosomal proteins.
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Project description:Exposure to certain stresses leads to readthrough transcription downstream of gene ends. Here we found that this phenomenon impacts the expression of genes located downstream to readthrough genes, whereby readthrough transcription proceeds into downstream genes, termed read-in genes. Using polyA-selected RNA-seq data from mouse fibroblasts, we identified widespread read-in in heat shock, oxidative and osmotic stress conditions. Read-in genes share distinctive genomic characteristics; they are extremely short, mainly due to less, shorter, introns, and they are highly GC rich. Furthermore, using ribosome footprint profiling we found that the translation of genes with high degrees of read-in is significantly reduced. Strikingly, read-in genes show extremely high levels of intron retention during stress, mostly in their first intron. While read-in genes share features that are generally associated with increased likelihood of intron retention, such as short introns and high GC content, intron retention in read-in genes during stress exceeds greatly beyond what is expected given their genomic properties. Finally, we found that first introns in read-in genes have weaker 5’ and 3’ splice sites. Our data portray a relationship between read-in and intron retention, suggesting it may have co-evolved to facilitate reduced translation of read-in genes during stress.
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Project description:15.5K is a RNA binding protein involved in the Minor Spliceosome. Here, we used shRNAs to knock down 15.5K in HEK293T cells to analysis the function of 15.5K in gene expression and intron retention.
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