# Project 3

> **NIH NIH P01** · UNIVERSITY OF FLORIDA · 2022 · $257,511

## Abstract

PROJECT SUMMARY/ABSTRACT
Classical immunogenetics, linkage studies, and genome-wide association studies (GWAS) have identified a set
of ~50 chromosomal regions that individually and significantly contribute to the risk for type 1 diabetes (T1D).
Knowledge of the genes in these regions provides an opportunity to probe the molecular underpinnings of the
disease, potentially facilitating improved disease prediction and/or novel strategies for prevention or therapeutic
intervention. ImmunoChip fine mapping in T1D indicates that the majority of credible causative genetic variants
for T1D overlap with tissue specific enhancer (but not promoter) elements, emphasizing the need for a context
dependent understanding of the mode of action for genes contributing to T1D pathogenesis (Projects 1 and 2)
as well as through the study of relevant cell types; an emerging notion for this P01 renewal (and the focus of
Project 2). To address this need, Project 3 has, in preliminary studies, processed more than 800 RNA-Seq
samples; transcriptionally profiling T and B lymphocyte subsets in both T1D cases and controls. These efforts
have yielded three key observations: 1) Genes located in T1D-associated chromosomal regions are significantly
enriched for cell-type specific alternative splicing events. These alternative splicing events include intron
retention or exon skipping activities that are likely to have significant effects on the expression and function of
the proteins encoded by these genes. 2) Identification of non-coding polymorphisms in regulatory regions that
are recognized as credible causative variants for T1D and are significantly associated with these alternative
splicing events in a highly tissue-specific manner. 3) Genes located in chromosomal regions associated with
T1D that display correlated expression in lymphocytes, allowing them be clustered into co-expression modules
that provide insights into regulation and function. Our preliminary findings suggest that transcript isoforms and,
by implication, the protein isoforms that they encode, are altered in T1D through genetically regulated shifts in
exon usage in specific cell types. To gain a comprehensive understanding of the impact of alternative splicing
and alternative transcript usage on T1D risk, and to identify and characterize disease relevant transcripts and
isoforms, we propose to apply long read sequencing to RNA from selected lymphocyte populations in T1D and
jointly analyze short and long read data to obtain reliable, cell type specific, information on transcript structure
and usage. We will then characterize the downstream effects of alternative splicing and transcript isoform usage
on a key T1D gene, IKZF4, which anchors a co-expression module in regulatory T cells. Finally, we will
characterize the impact of T1D causative genetic variants on chromatin accessibility and DNA methylation at the
T1D candidate genes they flank. These studies are highly synergistic with Projects 1 and 2 where t...

## Key facts

- **NIH application ID:** 10413002
- **Project number:** 5P01AI042288-24
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** MARK A. ATKINSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $257,511
- **Award type:** 5
- **Project period:** 1997-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413002

## Citation

> US National Institutes of Health, RePORTER application 10413002, Project 3 (5P01AI042288-24). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10413002. Licensed CC0.

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