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

The histone lysine methyltransferase G9a (Ehmt2) catalyzes the dimethylation of lysine 9 on histone 3 (H3K9me2) and is associated with gene repression. Here, we show that loss of G9a leads to dysregulated innate lymphoid cell (ILC) development and function. Group 2 ILCs (ILC2s) that produce IL-5 and IL-13 are severely reduced in mice with a hematopoietic cell-specific deficiency in G9a with a concomitant increase in ILC3s. Accordingly, type 2 immune responses in the lung are significantly reduced. Mechanistically, in developing immature ILC2s, G9a-dependent H3K9me2 is found at high levels at genes controlling ILC3 development. In the absence of G9a and H3K9me2, dysregulated ILC3 gene expression occurs resulting in heightened ILC3 gene expression and responses. Together, these results identify a novel epigenetic regulatory pathway that controls ILC2/ILC3 development.