Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA

Walter K Mowel; Sam J McCright; Jonathan J Kotzin; Magalie A Collet; Asli Uyar; Xin Chen; Alexandra DeLaney; Sean P Spencer; Anthony T Virtue; EnJun Yang; Alejandro Villarino; Makoto Kurachi; Margaret C Dunagin; Gretchen Harms Pritchard; Judith Stein; Cynthia Hughes; Diogo Fonseca-Pereira; Henrique Veiga-Fernandes; Arjun Raj; Taku Kambayashi; Igor E Brodsky; John J O'Shea; E John Wherry; Loyal A Goff; John L Rinn; Adam Williams; Richard A Flavell; Jorge Henao-Mejia

doi:10.1016/j.immuni.2017.08.012

Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA

Immunity. 2017 Sep 19;47(3):435-449.e8. doi: 10.1016/j.immuni.2017.08.012.

Authors

Walter K Mowel¹, Sam J McCright¹, Jonathan J Kotzin¹, Magalie A Collet², Asli Uyar², Xin Chen³, Alexandra DeLaney⁴, Sean P Spencer¹, Anthony T Virtue¹, EnJun Yang¹, Alejandro Villarino⁵, Makoto Kurachi⁶, Margaret C Dunagin⁷, Gretchen Harms Pritchard⁴, Judith Stein⁸, Cynthia Hughes⁸, Diogo Fonseca-Pereira⁹, Henrique Veiga-Fernandes¹⁰, Arjun Raj⁷, Taku Kambayashi¹, Igor E Brodsky⁴, John J O'Shea⁵, E John Wherry⁶, Loyal A Goff¹¹, John L Rinn¹², Adam Williams¹³, Richard A Flavell¹⁴, Jorge Henao-Mejia¹⁵

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
³ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
⁴ Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
⁶ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06510, USA.
⁹ Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisbon, Portugal.
¹⁰ Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisbon, Portugal; Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal.
¹¹ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
¹² Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
¹³ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Genetics and Genomic Sciences, University of Connecticut Health Center, Farmington, CT 06032, USA. Electronic address: adam.williams@jax.org.
¹⁴ School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu.
¹⁵ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jhena@mail.med.upenn.edu.

Abstract

Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs. Moreover, the Rroid locus, but not the lncRNA itself, controlled the identity and function of ILC1s by promoting chromatin accessibility and deposition of STAT5 at the promoter of Id2 in response to interleukin (IL)-15. Thus, non-coding elements responsive to extracellular cues unique to each ILC subset represent a key regulatory layer for controlling the identity and function of ILCs.

Keywords: ILC1; Id2; innate lymphoid cells; lineage identity; lncRNA; transcriptional regulation.

Publication types

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

MeSH terms

Animals
Cell Differentiation
Cell Lineage / genetics
Cell Lineage / immunology
Chromatin Assembly and Disassembly
Female
Gene Expression Profiling
Gene Expression Regulation*
Genetic Loci
Homeostasis
Immunity, Innate / genetics*
Inhibitor of Differentiation Protein 2 / genetics
Killer Cells, Natural / cytology
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Lymphocyte Subsets / immunology
Lymphocyte Subsets / metabolism
Lymphocytes / immunology
Lymphocytes / metabolism*
Male
Mice
Promoter Regions, Genetic
RNA, Long Noncoding / genetics*
Regulatory Sequences, Nucleic Acid*
STAT5 Transcription Factor / metabolism
Transcription, Genetic

Substances

Inhibitor of Differentiation Protein 2
RNA, Long Noncoding
STAT5 Transcription Factor

Abstract

Publication types

MeSH terms

Substances

Grants and funding