# Cis Regulatory Elements and Systemic Lupus Erythematosus

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $525,796

## Abstract

Project Summary/Abstract
Systemic lupus erythematosus (SLE, lupus) is a chronic inflammatory autoimmune disorder with a significant
genetic component. Genome wide association studies (GWAS) have identified many associated genetic
variants in SLE patients. Almost all are outside coding regions, in areas likely enriched for regulatory and
transcriptionally functional variants. T follicular helper cells (Tfh) and germinal center B (GCB) cells are major
contributors to systemic autoimmunity in SLE through their collaborative production of pathogenic
autoantibodies and subsequent immune-complex mediated tissue injury. Our preliminary and published studies
indicate that enhancers in Tfh and GCB cells and sites of occupancy by Bcl6 (B cell lymphoma 6), the
canonical transcriptional repressor necessary for differentiation and function of these cell types, co-localize
with gene variants associated with SLE. The goal of aim one of this revised application is to identify enhancer
elements controlling gene expression programs in Tfh and GCB cells. We will define and correlate chromatin
architecture, RNA polymerase II occupancy, and genomic organization with transcriptome analyses to identify
enhancers in primary human Tfh and GCB cells. After enhancer identification and validation, we will integrate
our data to identify and correlate cell-type specific enhancers with programs of gene expression. The goal of
aim two is the identification of common regulatory networks mediated by Bcl6 and its transcriptional repressor,
Blimp1 (B lymphocyte-induced maturation protein-1), in Tfh and GCB cells. Integration of transcriptome data,
genomic organization, histone architecture, and Bcl6 and Blimp1 occupancy will provide us detailed knowledge
of gene structure, function, and regulation controlled by these transcriptional repressors in Tfh and GCB cells.
The regulation of groups of genes in these data sets will be compared and contrasted, allowing us to identify
and characterize common regulatory networks controlled by the Blimp1-Bcl6 axis. The goal of aim three is the
identification and characterization of functional genetic variants associated with SLE in Tfh and GCB cells.
SLE-linked genetic variants will be integrated with transcriptome analyses, enhancer maps, Bcl6 and Blimp1
occupancy, chromatin accessibility assays, and genotype-specific gene expression to identify functional SNPs.
Functional studies of relevant enhancers will be performed including in vivo gene editing studies in mice using
CRISPR-Cas9 technology to genetically modify candidate regions in the murine genome to assess the
regulatory effects of these elements in Tfh and GCB cell differentiation and function. Identification of functional
genetic variants should facilitate development of novel therapeutic strategies for use in SLE patients.

## Key facts

- **NIH application ID:** 9980291
- **Project number:** 5R01AR068994-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Joseph Edgar Craft
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,796
- **Award type:** 5
- **Project period:** 2016-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980291

## Citation

> US National Institutes of Health, RePORTER application 9980291, Cis Regulatory Elements and Systemic Lupus Erythematosus (5R01AR068994-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980291. Licensed CC0.

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