# Mapping epigenetic regulatory circuits of Th17 pathogenicity in autoimmunedisease

> **NIH NIH F32** · BROAD INSTITUTE, INC. · 2020 · $69,306

## Abstract

Immune cells have diverse functions, from regulatory roles in tissue homeostasis to inflammatory
responses against foreign challenges. In autoimmune disease, affected immune cells acquire a pathogenic
state characterized by chronic activation of proinflammatory genes. CD4+ Th17 cells exemplify this functional
plasticity, acting as protective agents in gut function or harmful instigators of inflammation in autoimmune
disease. Th17 cells have been shown to be disease-causing agents in several autoimmune disorders affecting
>10 million Americans, including multiple sclerosis, inflammatory bowel disease, psoriasis, and rheumatoid
arthritis. Previous studies have revealed considerable heterogeneity in the ability of Th17 cells to induce
disease and become pathogenic in animal models of multiple sclerosis. My objective is to identify the
epigenetic regulatory mechanisms that control Th17 plasticity toward a pathogenic fate in autoimmune
disease. I hypothesize that Th17 effector function is encoded in the epigenome and this can be leveraged to
identify transcription regulators and remodeling events that distinguish the pathogenic state from regulatory
function in Th17 cells in autoimmune disease.
 By applying recent advances in massively parallel single-cell epigenomics, computational methods for
predicting transcription factor binding and deciphering single-cell variation, and technologies for targeted
genetic perturbation10,12,17, I will test my hypothesis through the following aims: (1) Use the assay for
transposase accessible chromatin (ATAC)-seq to identify an epigenetic signature defining the Th17 pathogenic
fate in the context of in vitro cytokine-induced Th17 polarization; (2) Characterize epigenetic heterogeneity in
Th17 pathogenic cell fate using single-cell ATAC-seq during experimental autoimmune encephalomyelitis, an
autoimmune disease model of multiple sclerosis, and use this heterogeneity to identify potential transcription
factor regulators of Th17 autoimmunity; and (3) Perform genetic perturbation experiments during Th17
polarization and measure impact on gene expression and chromatin accessibility in order to determine
mechanisms of candidate drivers for establishing the Th17 pathogenic fate.
 With these studies, I will reconstruct the epigenetic regulatory circuits, consisting of transcription
factors, target genes, and regulatory elements that control the disease-causing, pro-inflammatory cell fate of
Th17 cells. These studies will provide important insights into the epigenetic networks that control nuanced cell
function and reveal targeted strategies to reprogram immune cell pathogenic states in autoimmune disease
without affecting non-pathogenic Th17 function.

## Key facts

- **NIH application ID:** 9851810
- **Project number:** 5F32AI138458-03
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Pratiksha I Thakore
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2018-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851810

## Citation

> US National Institutes of Health, RePORTER application 9851810, Mapping epigenetic regulatory circuits of Th17 pathogenicity in autoimmunedisease (5F32AI138458-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851810. Licensed CC0.

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