Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation

Michaël F Michieletto; John J Tello-Cajiao; Walter K Mowel; Aditi Chandra; Sora Yoon; Leonel Joannas; Megan L Clark; Monica T Jimenez; Jasmine M Wright; Patrick Lundgren; Adam Williams; Christoph A Thaiss; Golnaz Vahedi; Jorge Henao-Mejia

doi:10.1038/s41590-022-01295-y

Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation

Nat Immunol. 2023 Jan;24(1):42-54. doi: 10.1038/s41590-022-01295-y. Epub 2022 Sep 1.

Authors

Michaël F Michieletto^#^{1

2}, John J Tello-Cajiao^#^{1

2

3

4}, Walter K Mowel^{1

2}, Aditi Chandra^{2

3

4}, Sora Yoon^{2

3

4}, Leonel Joannas^{1

2}, Megan L Clark^{1

2}, Monica T Jimenez^{1

2}, Jasmine M Wright^{1

2}, Patrick Lundgren^{2

5}, Adam Williams⁶, Christoph A Thaiss^{2

5}, Golnaz Vahedi^{7

8

9}, Jorge Henao-Mejia^{10

11

12}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁷ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. vahedi@pennmedicine.upenn.edu.
⁸ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. vahedi@pennmedicine.upenn.edu.
⁹ Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. vahedi@pennmedicine.upenn.edu.
¹⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jhena@pennmedicine.upenn.edu.
¹¹ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jhena@pennmedicine.upenn.edu.
¹² Division of Protective Immunity, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. jhena@pennmedicine.upenn.edu.

^# Contributed equally.

Abstract

Innate lymphoid cells (ILCs) are well-characterized immune cells that play key roles in host defense and tissue homeostasis. Yet, how the three-dimensional (3D) genome organization underlies the development and functions of ILCs is unknown. Herein, we carried out an integrative analysis of the 3D genome structure, chromatin accessibility and gene expression in mature ILCs. Our results revealed that the local 3D configuration of the genome is rewired specifically at loci associated with ILC biology to promote their development and functional differentiation. Importantly, we demonstrated that the ontogenesis of ILC2s and the progression of allergic airway inflammation are determined by a unique local 3D configuration of the region containing the ILC-lineage-defining factor Id2, which is characterized by multiple interactions between the Id2 promoter and distal regulatory elements bound by the transcription factors GATA-3 and RORα, unveiling the mechanism whereby the Id2 expression is specifically controlled in group 2 ILCs.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cell Lineage
Humans
Immunity, Innate*
Inflammation / genetics
Inflammation / metabolism
Lymphocytes*
Promoter Regions, Genetic

Abstract

Publication types

MeSH terms

Grants and funding