Increased chromatin accessibility facilitates intron retention in specific cell differentiation states

Area of Science:

• Molecular Biology
• Genomics
• Immunology

Background:

• Dynamic intron retention (IR) is crucial in vertebrate cells and linked to human diseases like cancer.
• Existing research on IR regulation by sequence, trans-regulatory, and epigenetic factors shows conflicting results, necessitating systematic analysis.

Purpose of the Study:

• To systematically analyze the role of epigenetic factors in regulating intron retention (IR) in primary human myeloid and lymphoid cells.
• To develop predictive models for IR regulation using multi-omics data and machine learning.

Main Methods:

• Integrated multi-omics data: mRNA sequencing (mRNA-Seq), whole-genome bisulfite sequencing (WGBS), nucleosome occupancy methylome sequencing (NOMe-Seq), and chromatin immunoprecipitation sequencing (ChIP-Seq).
• Employed machine learning to train models for predicting IR regulation.
• Analyzed primary human myeloid and lymphoid cells.

Main Results:

• Increased chromatin accessibility, indicated by nucleosome-free regions, substantially contributes to cell-specific intron retention.
• Intrinsic sequence features of introns are confirmed as key determinants for evading splicing.
• Established a link between chromatin architecture and IR regulation.

Conclusions:

• Chromatin architecture plays a significant role in regulating intron retention in innate immune cells.
• Findings offer insights into RNA processing alterations in disease and potential therapeutic targets for aberrant splicing.