Department of Biology, University of Kentucky, Lexington, KY 40506, USA.
Genes (Basel). 2021 Jul 29;12(8):1182. doi: 10.3390/genes12081182.
Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.
抑癌基因（TSG）对于多细胞生物的正常细胞功能至关重要，但许多 TSG 和肿瘤抑制机制仍然未知。扁形动物表现出特别强大的肿瘤抑制作用，但这种特性背后的具体机制尚不清楚。在这里，我们分析了整个扁形动物基因组中的组蛋白 H3 赖氨酸 4 三甲基化（H3K4me3）信号，以确定在哺乳动物细胞中标记必需的细胞身份基因和 TSG 的广泛 H3K4me3 染色质特征是否在这种有价值的体内干细胞功能模型中保守。我们发现，该特征确实在扁形动物基因组中保守，并且赖氨酸甲基转移酶 Set1 在细胞身份和推定的 TSG 基因座上都主要负责其产生。此外，我们表明在扁形动物中耗尽会诱导干细胞表型，表明 TSG 功能丧失，包括过度增殖和异常的 DNA 损伤反应（DDR）。重要的是，这项工作确立了 Set1 在扁形动物干细胞中靶向特定基因座，并为它们标记了保守的染色质特征。此外，我们的数据强烈表明，这些基因上的 Set1 活性在正常动态平衡和应对遗传毒性应激时都具有重要的功能后果。
