G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program

Innate lymphoid cells (ILCs) are emerging as important regulators of homeostatic and disease-associated immune processes. Despite recent advances in defining the molecular pathways that control development and function of ILCs, the epigenetic mechanisms that regulate ILC biology are unknown. Here, w...

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Bibliographic Details
Published in:The Journal of experimental medicine 2016-06, Vol.213 (7), p.1153-1162
Main Authors: Antignano, Frann, Braam, Mitchell, Hughes, Michael R, Chenery, Alistair L, Burrows, Kyle, Gold, Matthew J, Oudhoff, Menno J, Rattray, David, Halim, Timotheus Y, Cait, Alissa, Takei, Fumio, Rossi, Fabio M, McNagny, Kelly M, Zaph, Colby
Format: Article
Language:English
Subjects:
Animals
Epigenesis, Genetic - genetics
Epigenesis, Genetic - immunology
Gene Deletion
Hematopoietic Stem Cells
Histone-Lysine N-Methyltransferase - genetics
Histone-Lysine N-Methyltransferase - immunology
Histones - genetics
Histones - immunology
Immunity, Innate - physiology
Lymphocytes - immunology
Mice
Mice, Knockout
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Summary:Innate lymphoid cells (ILCs) are emerging as important regulators of homeostatic and disease-associated immune processes. Despite recent advances in defining the molecular pathways that control development and function of ILCs, the epigenetic mechanisms that regulate ILC biology are unknown. Here, we identify a role for the lysine methyltransferase G9a in regulating ILC2 development and function. Mice with a hematopoietic cell-specific deletion of G9a (Vav.G9a(-/-) mice) have a severe reduction in ILC2s in peripheral sites, associated with impaired development of immature ILC2s in the bone marrow. Accordingly, Vav.G9a(-/-) mice are resistant to the development of allergic lung inflammation. G9a-dependent dimethylation of histone 3 lysine 9 (H3K9me2) is a repressive histone mark that is associated with gene silencing. Genome-wide expression analysis demonstrated that the absence of G9a led to increased expression of ILC3-associated genes in developing ILC2 populations. Further, we found high levels of G9a-dependent H3K9me2 at ILC3-specific genetic loci, demonstrating that G9a-mediated repression of ILC3-associated genes is critical for the optimal development of ILC2s. Together, these results provide the first identification of an epigenetic regulatory mechanism in ILC development and function.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20151646