What does this research mean for the field?

During human pancreatic development, coordinated dynamic changes in RNA modifications—particularly the loss of m6A and 2OmeG—and transcript isoform usage regulate gene expression and lineage specification. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The research aims to understand how RNA modifications influence gene expression during pancreatic development, particularly in the context of diabetes.

June 7, 2026

2677-P: Dynamic Epitranscriptomic Regulation across the Developing Human Pancreas

Key Points

The research aims to understand how RNA modifications influence gene expression during pancreatic development, particularly in the context of diabetes.
Direct RNA sequencing (dRNA-seq) on human pancreas samples aged 10 - 21 post conception weeks.
Simultaneous detection of isoforms and eight RNA modifications during endocrine cell induction.
Immunohistochemical staining to identify spatial localization of modification readers.
>3,000 modifications with significant developmental dynamics were uncovered.
A global decrease in RNA modifications, with notable loss of m6A and 2OmeG during development.
Pancreas-specific genes showed enrichment in gains of m6A and Ψ, and losses of 2OmeG.

Abstract

Introduction and Objective: RNA modifications are crucial regulators of gene expression in human development. They have an established role in regulating β cell development and function, with dysregulation resulting in diabetes. Numerous limitations have restricted the study of these modifications directly in pancreatic tissue. We utilize a cohort of human fetal pancreatic samples to determine the role of RNA modifications and transcriptome diversity to inform mechanisms relevant to diabetes pathogenesis. Methods: We used direct RNA sequencing (dRNA-seq) on human pancreas samples spanning 10 - 21 post conception weeks. This enabled simultaneous detection of isoforms and eight RNA modifications (m6A, m5C, 2OmeA/T/G/C, pseudouridine (Ψ), inosine) during a critical window of endocrine cell induction. We also identified spatial localization of modification readers using immunohistochemical staining. Results: Gene level expression reveals induction of genes reflective of the establishment of endocrine and exocrine identity. Leveraging dRNA's long read capability revealed genes with distinct temporal isoform shifts that diverged from total expression. We identified 3,000 modifications with significant developmental dynamics. We observe a global decrease in RNA modifications across development with loss of m6A and 2OmeG the most predominant. We find a correlation with dynamic gene expression and dynamic modification, genes activated and repressed over the timecourse are associated with a gain and loss of m6A. Pancreas specific genes are enriched in gains in m6A and Ψ, and loss of 2OmeG. Finally, we identify developmental and cell type specific localization of modification readers within fetal pancreatic tissue. Conclusion: We find coordinated changes in transcript isoform usage and RNA modifications. Integrating transcriptome diversity, RNA modifications and reader localization provides insight into post-transcriptional regulation during pancreatic lineage specification. Our results provide context for interpreting genetic and epigenetic risk in diabetes. Disclosure A. MacCalman: None. S. Richardson: None. N. Owens: None.

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