Increased chromatin accessibility facilitates intron retention in specific cell differentiation states

Petrova, Veronika, Song, Renhua, DEEP Consortium, , Nordström, Karl J.V., Walter, Jörn, Wong, Justin J.-L., Armstrong, Nicola J., Rasko, John E.J., and Schmitz, Ulf (2022) Increased chromatin accessibility facilitates intron retention in specific cell differentiation states. Nucleic Acids Research, 50 (20). gkac994. pp. 11563-11579.

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Abstract

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 (RNA-seq), whole-genome bisulfite sequencing (WGBS), nucleosome occupancy methylome sequencing (NOMe-Seq), 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 of chromatin architecture in IR regulation. With an increasing 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.

Item ID: 76623
Item Type: Article (Research - C1)
ISSN: 1362-4962
Copyright Information: © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC 1177305, NHMRC 1080530, NHMRC 1128175, NHMRC 1129901, NHMRC 1126306, NHMRC 1196405
Date Deposited: 15 Nov 2022 04:34
FoR Codes: 31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310204 Genomics and transcriptomics @ 50%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310199 Biochemistry and cell biology not elsewhere classified @ 50%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 100%
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