# 3D genome organization of the Ets1-Fli1 locus controls allergic responses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $772,175

## Abstract

The goal of this proposal is to study how perturbation in three-dimensional (3D) genome folding alters CD4+ T
cell function, mediating allergic disorders. T cell identity depends on not only the linear genome sequence that
embeds millions of regulatory elements, but also the 3D chromatin architecture that orchestrates the spatial
localization of the regulatory elements with their target genes. Recent advances in our understanding of
nuclear organization indicate that single-nucleotide polymorphisms associated with immune-mediated diseases
may impact gene regulation through altered 3D genomic structure and reorganization of large genomic regions
in the disease relevant cell types. However, the link between sequence variation, cellular context, 3D genome
folding, and aberrant gene expression in majority of immune-mediated complex diseases remains largely
unknown. Our objective is to determine the molecular processes through which 3D genome
organization in T cells is linked to allergic disorders. We formulated this objective based on four
unexpected observations: (A) Our algorithmic definition of groups of densely interacting multi-enhancer
elements, which we called 3D cliques, revealed that a locus harboring the Ets1 and Fli1 genes is
hyperconnected in T cells. (B) This unique 3D genome architecture is conserved in human T cells coinciding
with multiple polymorphisms associated to type 2 immune diseases including allergy, asthma, and atopic
dermatitis. (C) We generated a novel strain of mice by deleting a non-coding sequence homologous to the
allergy-associated polymorphic region in the human genome, ~250kbp downstream of the Ets1 promoter. This
genetic deletion left T cell development intact but led to major defects in CD4+ T helper 1 (Th1) differentiation.
Th1 cells are responsible for the control of intracellular pathogens such as bacteria and dampen Th2
responses to allergens. Hence, limited Th1 differentiation due to genetic modification of the Ets1-Fli1 3D clique
may cause allergic responses. (D) We modeled the type 2 immune responses in vivo using house dust mites.
In the lung tissues of mice with a deletion in the non-coding sequence in the Ets1-Fli1 3D clique, we detected a
dramatic increase in allergic responses characterized by a significant accumulation of eosinophils and Th2
cells and a reduction in Th1 cells. These unpublished data provide us with compelling evidence that our
engineered mouse strain is a model for understanding the role of noncoding regulatory elements and 3D
genome folding in type 2 immune diseases. However, detailed cellular and molecular mechanisms through
which genetic deletion in the Ets1-Fli1 locus causes overt allergic responses remain to be understood.
Moreover, the generalizability of our 3D clique analysis to additional pathogenic regulatory nodes remains to
be examined. This work is significant because it is the first-ever mechanistic investigation providing a
connection between genome architecture and type...

## Key facts

- **NIH application ID:** 10885120
- **Project number:** 5R01AI168136-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jorge Henao-Mejia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $772,175
- **Award type:** 5
- **Project period:** 2023-07-10 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885120

## Citation

> US National Institutes of Health, RePORTER application 10885120, 3D genome organization of the Ets1-Fli1 locus controls allergic responses (5R01AI168136-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885120. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*