Increased chromatin accessibility facilitates intron retention in specific cell differentiation states
Published: 8 November 2022| Version 1 | DOI: 10.17632/b6crxbxbk2.1
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, , , , , , ,
Description
Dynamic intron retention (IR) in vertebrate cells is of widespread biological importance. Aberrant IR is associated with numerous human diseases including several cancers. Despite consistent reports demonstrating that intrinsic sequence features can help introns evade splicing, conflicting findings about cell type- or condition-specific IR regulation by trans-regulatory and epigenetic mechanisms demand an unbiased and systematic analysis of IR in a controlled experimental setting. We integrated matched mRNA sequencing (mRNA-Seq), whole-genome bisulfite sequencing (WGBS), nucleosome occupancy methylome sequencing (NOMeSeq) and chromatin immunoprecipitation sequencing (ChIP-Seq) data from primary human myeloid and
lymphoid cells. Using these multi-omics data and machine learning, we trained two complementary models to determine the role of epigenetic factors in the regulation of IR in cells of the innate immune system. We show that increased chromatin accessibility, as revealed by nucleosome-free regions, contributes substantially to the retention of introns in a cell-specific manner. We also confirm that intrinsic characteristics of introns are key for them to evade splicing. This study suggests an important role for chromatin architecture in IR regulation. With an in creasing appreciation that pathogenic alterations are linked to RNA processing, our findings may provide useful insights for the development of novel therapeutic approaches that target aberrant splicing.
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Steps to reproduce
R scripts required to reproduce the results can be found at:
https://github.com/combiomed/IR_code
Institutions
University of Sydney, James Cook University Australian Institute of Tropical Medicine, Universitat des Saarlandes, James Cook University, Curtin University, Centenary Institute
Categories
Alternative Splicing, Chromatin, Intron, DNA Methylation, Epigenetics, Nucleosome Positioning, Histone Modification
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2022-11-01T00:00:00.000Z
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Publication Title
Increased chromatin accessibility facilitates intron retention in specific cell differentiation states
Publication DOI
https://doi.org/10.1093/nar/gkac994
Citation
Petrova V, Song R, DEEP Consortium, Nordström KJV, Walter J, Wong JJ-L, Armstrong NJ, Rasko JEJ, Schmitz U. Increased chromatin accessibility facilitates intron retention in specific cell differentiation states. Nucleic Acids Research, 2022 1-17
Authors
Petrova V, Song R, DEEP Consortium, Nordström KJV, Walter J, Wong JJ-L, Armstrong NJ, Rasko JEJ, Schmitz U