Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 7, Pages 1153-1162Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151646
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Funding
- Canadian Institutes of Health Research's (CIHR) Canadian Epigenetics, Environment and Health Research Consortium [128090, MOP-84545, MSH-95368, MOP-89773, MOP-106623]
- Australian National Health and Medical Research Council [APP1004466]
- Leon Judah Blackmore Foundation
- CIHR/Canadian Association of Gastroenterology/Crohn's and Colitis Foundation of Canada postdoctoral fellowship
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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.
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