G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program.
G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program.
复制标题
DOI：
10.1084/jem.20151646
复制
发表时间：
2016-06-27
期刊：
影响因子：
--
通讯作者：
Zaph C
中科院分区：
文献类型：
--
作者：
Antignano F;Braam M;Hughes MR;Chenery AL;Burrows K;Gold MJ;Oudhoff MJ;Rattray D;Halim TY;Cait A;Takei F;Rossi FM;McNagny KM;Zaph C
Antignano， Zaph和合作者发现赖氨酸甲基转移酶G9a在决定第2组和第3组先天淋巴样细胞的发育程序中起关键作用。先天淋巴样细胞（ILCs）正在成为稳态和疾病相关免疫过程的重要调节因子。尽管最近在定义控制ILC发育和功能的分子途径方面取得了进展，但调节ILC生物学的表观遗传机制尚不清楚。在这里，我们确定了赖氨酸甲基转移酶G9a在调节ILC2发育和功能中的作用。造血细胞特异性G9a （Vav）缺失小鼠。G9a−/−小鼠)外周部位ILC2s严重减少，与骨髓中未成熟ILC2s发育受损有关。因此,变风量空调。G9a−/−小鼠对过敏性肺炎症的发展具有抗性。g9a依赖性组蛋白3赖氨酸9 （H3K9me2）二甲基化是一种与基因沉默相关的抑制性组蛋白标记。全基因组表达分析表明，G9a的缺失导致ILC2群体中ilc3相关基因的表达增加。此外，我们在ilc3特异性基因位点上发现了高水平的g9a依赖性H3K9me2，这表明g9a介导的ilc3相关基因的抑制对ILC2s的最佳发育至关重要。总之，这些结果首次确定了ILC发育和功能的表观遗传调控机制。
Antignano, Zaph, and collaborators show that the lysine methyltransferase G9a plays a critical role in determining the developmental programs of group 2 and 3 innate lymphoid cells. 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.