Intestine-to-Germline Transmission of Epigenetic Information Intergenerationally Ensures Systemic Stress Resistance in C.elegans.

Epigenetic states are metastable and changed throughout life, and their changes play a major role in the regulation of organismal homeostasis, including stress resistance. However, the mechanisms coordinating epigenetic states and systemic stress resistance across tissues remain largely unknown. Here, we identify the intestine-to-germline communication of epigenetic states, which enhances stress resistance transgenerationally in C. elegans. We firstly show that the alteration in epigenetic states by deficiency of the histone H3K4me3 modifier ASH-2 in the intestine or germline increases organismal oxidative stress resistance, which is abrogated by knockdown of the H3K4 demethylase RBR-2 in the same tissue. Remarkably, the increase in stress resistance induced by ASH-2 deficiency in the intestine is abrogated by RBR-2 knockdown in the germline, suggesting the existence of inter-tissue transmission of epigenetic information from intestine to germline. Simultaneously, this intestine-to-germline communication in the parental generation transgenerationally provides the increase in stress resistance of the descendants for over two generations. Further analyses reveal that the inter-tissue communication requires the insulin/IGF-1 signaling effector DAF-16/FOXO in the intestine and is mediated, at least in part, by transcriptional regulation of F08F1.3, one of the intestinal ASH-2 target genes. These results unveil the novel intestine-to-germline communication of epigenetic information that provides the transgenerational regulation of organismal stress resistance. To further investigate the molecular mechanisms underlying intestine-to-germline communication, we sought the gene expression changes in the intestine ash-2 knockdown worms.表观遗传状态（epigenetic states）具有亚稳定性且伴随生命进程动态改变，其变化在包括抗逆性在内的机体稳态调控中发挥核心作用。然而，协调跨组织表观遗传状态与系统性抗逆性的分子机制仍未得到充分阐明。本研究鉴定出肠道向生殖系传递的表观遗传状态交流机制，该机制可在秀丽隐杆线虫（C. elegans）中实现跨代提升抗逆性。我们首先证实，在肠道或生殖系中缺失组蛋白H3K4me3修饰酶ASH-2所引发的表观遗传状态改变，可提升机体的氧化应激抗性，且该效应可被同一组织内H3K4去甲基化酶RBR-2的敲低所阻断。值得注意的是，肠道ASH-2缺失诱导的抗逆性提升，可被生殖系中RBR-2的敲低所抵消，这表明表观遗传信息从肠道向生殖系存在组织间传递现象。与此同时，亲本代的肠道-生殖系信号交流可跨代提升后代的抗逆性，该效应可持续超过两代。进一步分析显示，这种组织间信号交流需要肠道内的胰岛素/IGF-1信号效应因子DAF-16/FOXO参与，且至少部分通过肠道ASH-2靶基因之一的F08F1.3的转录调控实现。上述结果揭示了一种全新的肠道-生殖系表观遗传信息交流机制，该机制可实现对机体抗逆性的跨代调控。为进一步探究肠道-生殖系信号交流的分子机制，我们对肠道ash-2敲低的秀丽隐杆线虫的肠道组织开展了基因表达变化分析。