# 3-Dimensional genomic architecture in innate lymphoid cells and allergic inflammation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $645,276

## Abstract

PROJECT SUMMARY
Group 1, 2, and 3 innate lymphoid cells (ILC1, ILC2, and ILC3) are immune effector cells that contribute to tissue
homeostasis and host defense against nearly all classes of pathogens, but their dysregulation also play key roles
in prevalent diseases such as cancer, obesity, asthma, and colitis. The transcription factor (TF) networks that
control the development and functions of the different groups of ILC have recently been identified. Yet how the
chromatin accessibility landscape and the 3-dimensional (3D) genome architecture determine the development,
homeostasis, and effector functions of ILC is largely unknown. Thus, the overarching goal of this proposal is
to uncover how the 3D genomic and epigenetic architecture regulate the development of each ILC subset
and to the development of allergic airway inflammation. It is now well-stablished that the transcriptional
repressor Id2 determines the commitment and identity of the ILC lineage. As such, Id2 expression is now
considered a hallmark of all ILC subsets in mice and humans. Our preliminary data indicates that Id2 expression
is controlled in ILC1, but not ILC2 or ILC3, by specific long-range DNA interacting loops between specific distal
cis-regulatory elements (cis-RE) and the Id2 promoter. Moreover, we showed that ablation of these promoter-
cis-RE interactions in mice leads to a dramatic reduction in ILC1 in multiple tissues, while the development and
functions of ILC2 and ILC3 were unaltered. Thus, our findings indicate for the first time that Id2 expression is
regulated by long-range DNA interacting loops between the Id2 promoter and distal cis-RE in an ILC-subset
specific manner. Moreover, it indicates that ablating these cis-RE is a powerful strategy to generate genetic tools
to study the roles of each ILC subset in the context of an otherwise intact immune system. Yet how the chromatin
accessibility landscape and the 3D genomic architecture determines Id2 expression specifically in ILC2 and ILC3
remains unknown. Thus, in aims 1 and 2 of this project, we will use novel genetic tools that we generated, single
cell sequencing technologies, and HiC to elucidate how chromatin folding and accessibility determine the
development and functions of ILC2 and ILC3 through the regulation of Id2 expression. In aim 3, we will exploit
the specificity of these regulatory mechanisms to study the functions of ILC2 during allergic airway inflammation
in the context of an otherwise intact immune system. Collectively, these studies will answer the long-standing
question of how Id2 expression is controlled to drive the ILC fate. Moreover, it will generate an atlas of the 3D
genomic landscape of each ILC subset, which
that
will allow us to identify unknown non-coding regulatory regions
are critical for the function and development ILC1, ILC2, and ILC3.Importantly, through the identification of
specific regulatory mechanisms in each ILC subset, we have created novel mouse genetic tools to study...

## Key facts

- **NIH application ID:** 10417585
- **Project number:** 1R01AI168240-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jorge Henao-Mejia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $645,276
- **Award type:** 1
- **Project period:** 2022-06-20 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417585

## Citation

> US National Institutes of Health, RePORTER application 10417585, 3-Dimensional genomic architecture in innate lymphoid cells and allergic inflammation (1R01AI168240-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10417585. Licensed CC0.

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