# Chromatin Accessibility and Transcription Factor Networks in Rheumatoid Arthritis

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as a destructive
synovitis. In spite of the prominence of the synovial inflammation, many immunological abnormalities are
systemic. Autoantibodies are not tissue-specific and are directed against global antigens such as Ig Fc
determinants and neoantigens of citrullinated peptides. T cell abnormalities in RA are already detectable in
naïve T cells. Naïve T cells from RA patients have a lowered signaling threshold of the T cell receptor which
may explain why failure in immune tolerance to neoantigens such as citrullinated peptides is the
immunological hallmark of RA. They have defects in DNA repair mechanisms which predisposes for
increased apoptosis susceptibility and accelerated immunosenescence. And they have rewired their
metabolic network shunting glucose preferentially into the pentose phosphate pathway to reduce oxidative
stress and produce metabolites necessary for synthetic activities. This application aims at gaining a deeper
understanding of T cell dysfunction in RA by characterizing their epigenetic landscape. We will use a
recently developed platform, assay for transposase accessible chromatin (ATAC)-sequencing that allows
genome-wide mapping of the open chromatin within small populations of isolated T cells including antigen-
specific T cells. [Three aims are proposed. The objective of Aim 1 is to identify RA-associated epigenetic
signatures in naïve T cells by comparing patients with RA, psoriatic arthritis and age-matched controls and
relate them to the signatures in memory T cells and autoantigen-specific T cells. Aim 2 will explore the
influence of disease activity and treatment on these signatures. By examining transcription factor (TF) target
sequences at accessible sites, we will define transcription factor networks that are associated with RA
and/or related to cytokine exposure in peripheral blood or the synovial tissue. In Aim 3, we will explore the
functional consequences of differential chromatin accessibility by comparing open sites to the transcriptome
of T cell subsets before and after activation. In addition, we will determine the relationship of open sites to
eQTLs and to causal SNPs implicated in RA. These studies will provide a comprehensive map of promoter
and enhancer accessibilities in RA T cells that may determine the transcriptome at resting stage as well as
their ability to respond and develop into autoantigen-specific effector T cells.]

## Key facts

- **NIH application ID:** 9814668
- **Project number:** 5I01BX001669-08
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** JORG J GORONZY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814668

## Citation

> US National Institutes of Health, RePORTER application 9814668, Chromatin Accessibility and Transcription Factor Networks in Rheumatoid Arthritis (5I01BX001669-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9814668. Licensed CC0.

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