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, 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.
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada colby.zaph@monash.edu frann@brc.ubc.ca.
Frann
0000-0003-0502-5330
F
Antignano
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Mitchell
0000-0002-3038-5859
M
Braam
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Michael R
0000-0002-7925-6070
MR
Hughes
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Alistair L
AL
Chenery
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Kyle
K
Burrows
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Matthew J
MJ
Gold
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Menno J
0000-0002-1180-8975
MJ
Oudhoff
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
David
0000-0002-2444-0663
D
Rattray
The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Timotheus Y
0000-0001-9773-0023
TY
Halim
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Alissa
A
Cait
The Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Fumio
0000-0002-3620-5046
F
Takei
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Fabio M
FM
Rossi
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Kelly M
0000-0003-4737-3499
KM
McNagny
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia colby.zaph@monash.edu frann@brc.ubc.ca.
Colby
0000-0002-9889-9848
C
Zaph
D000818:Animals; D044127:Epigenesis, Genetic / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000276:immunology*; D006657:Histones / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000502:physiology*; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout
D006657:Histones; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase