# Altered chromatin accessibility in lamina propria macrophages in Crohn’s disease

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $37,210

## Abstract

Abstract
Crohn’s disease (CD) is a chronic, heterogeneous inflammatory disease that causes damage to the
gastrointestinal tract. There is no cure for CD. Research that furthers our understanding of CD may give rise to
more effective diagnostic markers and therapeutics. Macrophages are an integral part of the immune system.
Their job is to engulf harmful microbes, digest them and prime T cells and B cells for an adaptive response.
There are marked differences in lamina propria macrophage (LP MΦ) function in health when compared with
CD. LP MΦs from CD patients have the ability to secrete inflammatory cytokines and promote Th1 and Th17
immune responses, while LP MΦs in health promote more protective T cell responses. The molecular
mechanism giving rise to abnormal LP MΦs in CD patients remains poorly understood. I hypothesize that altered
chromatin accessibility drives the LP MΦ phenotypic changes that are associated with colitis phenotypes/CD.
This hypothesis will be tested through two aims. Aim 1 will determine if manipulation of LP MΦ accessible
chromatin in Il10-/- macrophages is sufficient to restore the physiological LP MΦ phenotype. Using a high-
throughput small molecule screen I determined that inhibitors of bromodomain and extra-terminal domain
proteins, such as (+)-JQ1, are sufficient to alter accessible chromatin and prevent inflammation in Il10-/-
macrophages. I will evaluate the ability of (+)-JQ1 to decrease genome-wide chromatin accessibility at IL-10
variable accessible regions and to prevent inflammatory cytokine secretion in vitro. I will also determine if
treatment of germ free Il10-/- mice with (+)-JQ1 is sufficient to prevent onset of colitis after colonization with
specific-pathogen free bacteria. In Aim 2 I will identify and functionally characterize the LP MΦ regulatory
program associated with human CD. For the first part of Aim 2, I will isolate LP MΦs from healthy and CD patients
and determine genome-wide changes in chromatin accessibility by ATAC-seq and gene expression by RNA-seq
in matched unstimulated and bacterially-stimulated samples. For the second part of Aim 2, I will quantify the
strength of select accessible chromatin regions based on their macrophage-specificity, known involvement in
inflammatory signaling pathways and if they are known to contain CD associated variants. I will evaluate the
ability of these selected regions to bind transcription factors using electrophoretic mobility shift assays and will
evaluate their impact on levels of transcription by luciferase reporter assays. Together, these aims will highlight
that changes in LP MΦ chromatin accessibility contributes significantly to altered LP MΦ function in the
pathogenesis of CD and fulfil my technical requirements as a Ph.D. candidate in the curriculum in Genetics and
Molecular Biology.

## Key facts

- **NIH application ID:** 10064967
- **Project number:** 5F31DK122704-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Michelle Sarah Hoffner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,210
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064967

## Citation

> US National Institutes of Health, RePORTER application 10064967, Altered chromatin accessibility in lamina propria macrophages in Crohn’s disease (5F31DK122704-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10064967. Licensed CC0.

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