Transcriptome-wide N6-methyladenosine methylation dynamic profile in type 1 diabetes progression

Area of Science:

• Epigenetics
• Molecular Biology
• Immunology

Background:

• Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic beta cells.
• Epigenetic modifications, such as N6-methyladenosine (m6A) methylation, play crucial roles in gene regulation and cellular function.
• Understanding the dynamic changes in m6A profiles during T1D progression is essential for identifying potential therapeutic targets.

Purpose of the Study:

• To comprehensively map the transcriptome-wide m6A profile at different stages of T1D development.
• To investigate the relationship between m6A modifications, mRNA expression, and associated signaling pathways in T1D pathogenesis.

Main Methods:

• Analysis of RNA from non-obese diabetic (NOD) mice at pre-diabetes and diabetes stages using MeRIP-seq and mRNA-seq.
• Bioinformatic analyses including m6A motif enrichment, differential methylation analysis, gene ontology, and pathway analysis.
• In vitro experiments using INS-1 cells to assess the impact of cytokine stimulation on m6A methylation and key regulatory enzymes.

Main Results:

• A progressive increase in m6A methylation sites and unique peaks was observed throughout T1D progression.
• The predominant m6A motif shifted from "GGACU" to "GGACU/A" as diabetes developed, with enrichment at start codons, coding regions, and stop codons.
• Distinct m6A and mRNA expression changes were identified in pre-diabetes and diabetes groups compared to controls.
• Pathway analysis revealed enrichment in insulin signaling, apoptosis, T-cell activation, and inflammation-related pathways, with additional pathways like Wnt and angiogenesis becoming involved as the disease progressed.
• In vitro studies showed that cytokine stimulation increased m6A methylation and modulated METTL3 and ALKBH5 expression.

Conclusions:

• m6A methyl group dynamics are altered during T1D disease progression.
• These dynamic m6A changes may influence mRNA expression and signal transduction pathways critical to T1D pathogenesis.
• The findings highlight the potential role of m6A modifications as regulators in T1D development.