Single-cell Multiome and Spatial Profiling Reveals Pancreas Cell Type-specific Gene Regulatory Programs Driving Type 1 Diabetes Progression

Overview

Journal bioRxiv

Date 2025 Mar 3

PMID 40027657

Authors

Rebecca Melton

Sara Jimenez

Weston Elison

Luca Tucciarone

Abigail Howell

Gaowei Wang

Denise Berti

Elisha Beebe

Michael Miller

Chun Zeng

Carolyn McGrail

Kennedy VanderStel

Katha Korgaonkar

Ruth Elgamal

Hannah Mummey

Joshua Chiou

Emily Griffin

Irina Kusmartseva

Mark Atkinson

Sebastian Preissl

Fabian J Theis

Maike Sander

Kyle J Gaulton

Affiliations

Soon will be listed here.

Abstract

Cell type-specific regulatory programs that drive type 1 diabetes (T1D) in the pancreas are poorly understood. Here we performed single nucleus multiomics and spatial transcriptomics in up to 32 non-diabetic (ND), autoantibody-positive (AAB+), and T1D pancreas donors. Genomic profiles from 853,005 cells mapped to 12 pancreatic cell types, including multiple exocrine sub-types. Beta, acinar, and other cell types, and related cellular niches, had altered abundance and gene activity in T1D progression, including distinct pathways altered in AAB+ compared to T1D. We identified epigenomic drivers of gene activity in T1D and AAB+ which, combined with genetic association, revealed causal pathways of T1D risk including antigen presentation in beta cells. Finally, single cell and spatial profiles together revealed widespread changes in cell-cell signaling in T1D including signals affecting beta cell regulation. Overall, these results revealed drivers of T1D progression in the pancreas, which form the basis for therapeutic targets for disease prevention.

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