# Enhancer-based Immune and Beta Cell Dysregulation Underlying T1D Risk

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $1,193,316

## Abstract

Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated and
inflammatory cytokines lead to loss of the insulin-producing β cells in the pancreas. Genome-wide association
studies (GWAS) have identified ~60 genomic regions associated with T1D risk. The vast majority of GWAS risk
variants associated with T1D reside in non-coding regions, particularly enhancers, suggesting that gene
regulatory changes substantially contribute to inter-individual differences in susceptibility to T1D. Driven by our
T1D GWAS annotation data, highlighting the importance of a systematic analysis of both immune and β
cell systems of both T1D patients and controls, we propose to identify causal enhancer variants and causal
target genes using contemporary computational methods and cutting-edge global genomics. We will perform our
PRO-cap and PRO-seq assays to comprehensively identify active enhancers harboring T1D-associated variants
in T cells, monocytes and stem cell derived β cells (sc-β cells) from T1D patients and controls, followed by
validation of active enhancers harboring T1D-associated variants using our eSTARR-seq assays (Aim 1). We
will perform our Tri-HiC assays to profile the enhancer-promoter interactomes at unprecedented high resolution
in primary T cells, primary monocytes and sc-β cells from T1D patients and controls as well as pancreatic islets
to comprehensively identify target genes of T1D-associated variants, and refine targets of T1D-associated
variants with T1D-sepcific alteration in target gene expression in each cell type using our coupled single cell
nucleus (sn) RNA-seq and snATAC-seq assays (Aim 2). We will validate targets of T1D-associated variants in
T cells, monocytes and β cells using CRISPR/Cas9 endogenous enhancer mutational strategies in the context
of the endogenous chromatin landscape in each cell type. Our analytical and experimental framework represents
an exciting new paradigm for studying T1D, and the subsequent clinical research based on our results has the
potential to develop preventive and therapeutic strategies against T1D. The data sets generated by these studies
will represent important, but currently lacking, resources for the T1D research community.

## Key facts

- **NIH application ID:** 10157356
- **Project number:** 1R01DK127778-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Dieter Meinrad Egli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,193,316
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10157356

## Citation

> US National Institutes of Health, RePORTER application 10157356, Enhancer-based Immune and Beta Cell Dysregulation Underlying T1D Risk (1R01DK127778-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10157356. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*