The Histone Methyltransferase SUV39H1 Suppresses Embryonal Rhabdomyosarcoma Formation in Zebrafish

Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRASG12D-driven zebrafish model for RMS. Here, we describe the identification of a histone H3 lysine 9 histone methyltransferase, SUV39H1, as a suppressor of embryonal RMS formation in zebrafish. This suppression is specific to the histone methyltransferase activity of SUV39H1, as point mutations in the SET domain lacked the effect. SUV39H1-overexpressing and control tumors have a similar proliferation rate, muscle differentiation state, and tumor growth rate. Strikingly, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. We demonstrate that the delayed tumor onset occurs between 5 and 7 days post fertilization. Gene expression profiling at these stages revealed that in the context of KRASG12D overexpression, SUV39H1 may suppress cell cycle progression. Our studies provide evidence for the role of SUV39H1 as a tumor suppressor.表观遗传学（Epigenetics）指不依赖DNA序列的、可逆转且可遗传的基因调控标记，涵盖DNA与组蛋白上的染色质修饰，其重要性不亚于DNA序列本身。染色质修饰因子在肿瘤发生过程中的作用愈发关键，在儿童横纹肌肉瘤（pediatric rhabdomyosarcomas, RMS）中尤为突出，相关研究也揭示了潜在的新型治疗靶点。本研究在KRASG12D驱动的横纹肌肉瘤斑马鱼模型中开展了染色质修饰因子的过表达筛选实验。在此，我们证实组蛋白H3赖氨酸9组蛋白甲基转移酶（histone H3 lysine 9 histone methyltransferase, SUV39H1）可抑制斑马鱼胚胎型横纹肌肉瘤的发生。该抑制作用特异性依赖于SUV39H1的组蛋白甲基转移酶活性，SET结构域的点突变会使其丧失该抑制功能。过表达SUV39H1的肿瘤与对照组肿瘤在增殖速率、肌肉分化状态及肿瘤生长速率上均无显著差异。值得注意的是，过表达SUV39H1的斑马鱼肿瘤起始发生率更低，这正是实验中观察到的抑制表型的成因。我们证实，肿瘤发生延迟的时间段为受精后5至7天。对该阶段的基因表达谱分析显示，在KRASG12D过表达的背景下，SUV39H1可抑制细胞周期进程。本研究为SUV39H1作为肿瘤抑制因子的功能提供了实验依据。