# Discovery of aberrant enhancer activities during gut development that underlie genetic predisposition to pediatric Crohn's disease

> **NIH NIH R21** · CORNELL UNIVERSITY · 2022 · $235,500

## Abstract

PROJECT SUMMARY: Crohn’s disease (CD) is a specific type of inflammatory bowel disease that occurs in
patients of all ages, with the distal region of the small intestine (referred to as ileum) as one of the most commonly
affected locations. It afflicts nearly a million people in the United States and is dramatically increasing in
prevalence worldwide. Notably, a substantial proportion of CD patients (~25%) are childhood- or adolescent-
onset, referred to as pediatric CD, which often display highly aggressive symptoms and more complicated clinical
course compared to late-onset, adult CD. Large-scale genetic studies of human populations have revealed >200
risk loci in the genome that are associated with CD, the vast majority of which occur in non-coding regions.
Although it is widely conjectured that these likely impact regulatory elements, this has not yet been definitively
demonstrated for most loci. Moreover, the extent to which the risk loci may affect gut development is unknown
and poorly explored, but merits investigation given the importance of developmental aberrations to other
inflammatory disorders of the gut. Notably, intractable congenital diarrhea in infants was very recently linked to
the deletion of a regulatory element that is transiently active during prenatal gut development. This study aims
to (1) define CD-risk loci harboring regulatory elements that are transiently active in pre-natal development and
(2) provide functional evidence for a specific CD risk allele affecting regulatory element activity during early gut
development, with the ultimate goal of offering a novel perspective on the etiology of pediatric CD. In the first
Aim, to study the contribution of CD-associated single nucleotide polymorphisms (SNPs) to early gut
development, we will leverage the recent technology of directed differentiation from human pluripotent stem cells
(hPSCs) into human intestinal spheroids followed by maturation into organoids (HIOs). This model exhibits
molecular features closely resembling the primary human fetal gut. To define active regulatory elements
genome-wide, we will apply a cutting-edge technology called chromatin run-on sequencing (ChRO-seq) to the
hPSC-HIO model as well as to pediatric and adult CD and non-CD ileal biopsies. We will then define those
regulatory elements that overlap CD risk loci and are active only in the pre-natal stages of the hPSC-HIO model
but not in the post-natal pediatric/adult tissue. In the second Aim, we will define the role of a specific CD-SNP
containing regulatory element within the PRDM1 locus during early gut development. In mouse, Prdm1 regulates
gut maturation, including the development of Paneth cells, which play important roles in CD pathobiology. We
have identified a regulatory element within the human PRDM1 gene that contains a CD-associated SNP and is
active only in pre-natal stages and not in adult CD or non-CD ileum. We will use CRISPR/Cas9 single-nucleotide
base editing technology to exa...

## Key facts

- **NIH application ID:** 10494257
- **Project number:** 5R21HD104922-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Praveen Sethupathy
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,500
- **Award type:** 5
- **Project period:** 2021-09-24 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10494257

## Citation

> US National Institutes of Health, RePORTER application 10494257, Discovery of aberrant enhancer activities during gut development that underlie genetic predisposition to pediatric Crohn's disease (5R21HD104922-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10494257. Licensed CC0.

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