Increased chromatin accessibility facilitates intron retention in specific cell differentiation states

Increased chromatin accessibility facilitates intron retention in specific cell differentiation states.

[thumbnail of gkac994.pdf] Text

Download (4MB)
Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Nucleic Acids Research
Volume: 50
Number: 20
Page Range: pp. 11563-11579
Date: 11 November 2022
Divisions: Computational BioMedicine
Epigenetics and RNA Biology
Gene and Stem Cell Therapy
Depositing User: General Admin
Identification Number: 10.1093/nar/gkac994
ISSN: 0305-1048
Date Deposited: 17 Apr 2023 00:52

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 (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 for 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.

Petrova, Veronika
Song, Renhua
Nordström, Karl J V
Walter, Jörn
Wong, Justin J L
Armstrong, Nicola J
Rasko, John E J
Schmitz, Ulf
Last Modified: 17 Apr 2023 00:52

Actions (login required)

View Item View Item