Division of Clinical Dermatology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Dermfocus, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
J Cell Biol. 2021 Apr 5;220(4). doi: 10.1083/jcb.201908178.
Epigenetic histone trimethylation on lysine 9 (H3K9me3) represents a major molecular signal for genome stability and gene silencing conserved from worms to man. However, the functional role of the H3K9 trimethylases SUV39H1/2 in mammalian tissue homeostasis remains largely unknown. Here, we use a spontaneous dog model with monogenic inheritance of a recessive SUV39H2 loss-of-function variant and impaired differentiation in the epidermis, a self-renewing tissue fueled by stem and progenitor cell proliferation and differentiation. Our results demonstrate that SUV39H2 maintains the stem and progenitor cell pool by restricting fate conversion through H3K9me3 repressive marks on gene promoters encoding components of the Wnt/p63/adhesion axis. When SUV39H2 function is lost, repression is relieved, and enhanced Wnt activity causes progenitor cells to prematurely exit the cell cycle, a process mimicked by pharmacological Wnt activation in primary canine, human, and mouse keratinocytes. As a consequence, the stem cell growth potential of cultured SUV39H2-deficient canine keratinocytes is exhausted while epidermal differentiation and genome stability are compromised. Collectively, our data identify SUV39H2 and potentially also SUV39H1 as major gatekeepers in the delicate balance of progenitor fate conversion through H3K9me3 rate-limiting road blocks in basal layer keratinocytes.
组蛋白赖氨酸 9 三甲基化 (H3K9me3) 的表观遗传修饰代表了从蠕虫到人普遍存在的基因组稳定性和基因沉默的主要分子信号。然而，哺乳动物组织稳态中 H3K9 三甲基转移酶 SUV39H1/2 的功能作用在很大程度上仍是未知的。在这里，我们利用一种自发的犬种模型，该模型具有隐性 SUV39H2 功能丧失变异的单基因遗传和表皮分化受损的特征，而表皮是一种自我更新的组织，由干细胞和祖细胞的增殖和分化所驱动。我们的研究结果表明，SUV39H2 通过在编码 Wnt/p63/黏附轴组件的基因启动子上形成 H3K9me3 抑制性标记来限制命运转化，从而维持干细胞和祖细胞库。当 SUV39H2 功能丧失时，抑制作用被解除，增强的 Wnt 活性导致祖细胞过早退出细胞周期，这一过程在原代犬、人和小鼠角蛋白细胞中通过药理学 Wnt 激活得到模拟。结果，培养的 SUV39H2 缺陷型犬角蛋白细胞的干细胞生长潜力耗尽，而表皮分化和基因组稳定性受到损害。总的来说，我们的数据表明 SUV39H2 （可能还有 SUV39H1）作为主要的调控因子，通过 H3K9me3 限速性路障来维持基底细胞层中祖细胞命运转化的微妙平衡。
