精子中组蛋白修饰H3K4me3在跨代遗传中的作用

Environmental exposure of parents, such as chemical exposure, changes in eating habits and mental stimulation, may influence the phenotype of offspring by affecting epigenome of sperm. The role of sperm and embryo epigenome in phenotype inheritance is unclear. A recent study found that some of the sperm H3K4me3 marker can escaped the epigenetic reprogramming during early embryonic development. Our previous study found that exposure of the embryo (F1) to the pesticide atrazine (ATZ) led to global differential gene expression in F3 testis, liver and brain, and the global changes of histone marker H3K4me3 can explain some of the differential expressed genes. In this project, based on H3K4me3 ChIP-seq data in mouse sperm, early embryonic development and primordial germ cells, we will detect the H3K4me3 peaks that are enriched in sperm and can escape epigentic reprograming during early embryonic development and primordial germ cell development. Conbine the data from our previous study, we can identify the heritable H3K4me3 sites that are sensitive to ATZ embryonic exposure. Further analysis of the RNA-seq data from the testis, liver and brain of F3 male mice will provide mechanistic insights in how the H3K4me3 markers might be inherited and effect genes expression in next generations.

亲代的环境因素暴露，如化学物质接触、饮食习惯改变和精神刺激等，可能通过影响精子表观遗传信息而影响后代的表型。精子及受精后的表观遗传机制在传递亲本性状过程中的作用并不清楚。最近的研究发现部分精子中H3K4me3标志逃脱了胚胎早期发育的表观遗传重编程。我们前期研究发现胚胎（F1）暴露于农药莠去津（ATZ）会引起F3睾丸、肝和脑基因表达发生全局性改变，并且睾丸中差异的RNA表达与组蛋白H3K4me3标志的全局变化有关。本项目中，我们将从小鼠精子富集的H3K4me3位点中筛选可以逃避胚胎发育过程中两轮表观遗传标志的重编程，而从亲代遗传到子代的H3K4me3基因组位点。在前期关于ATZ跨代遗传效用研究的基础上，发现对ATZ暴露敏感的可遗传H3K4me3 位点。进一步结合F3雄性小鼠睾丸、肝和脑的RNA-seq数据提出由ATZ暴露诱导的差异H3K4me3信号跨代遗传并影响后代基因表达的分子机制。

小鼠胚胎暴露于农药莠去津(ATZ)降低了后代睾丸组织中组蛋白修饰标志H3K4me3信号，并增加了第三代小鼠多器官可变剪接 RNA 的表达。编码差异表达的可变剪接转录本的基因的启动子中富集了转录因子SP)家族基序。本项目对小鼠精子、小鼠植入前胚胎发育阶段和雄性性腺原始生殖细胞 (PGC) 的 H3K4me3 染色质免疫沉淀测序 (ChIP-seq) 数据进行了分析，以确定父本重编程逃避 H3K4me3 区域 (RER)。通过分析发现 251 个在精子中富集 H3K4me3 标记的区域，在胚胎早期发育期间的父本基因组和雄性性腺 PGC 中都保留信号。说明这251个RER可逃避胚胎发育早期和原始生殖细胞发育过程中的表观遗传重编程。进一步分析发现，179 个基因在转录起始位点 (TSS) 的 1 kb 内具有 RER。这些基因在基因本体术语“RNA剪接”中显著富集，并且SP1/SP2/SP3基序在RER相关的H3K4me3峰中富集。总体而言，RNA 剪接基因 TSS 中的 H3K4me3 标记在两轮表观遗传重编程过程中保留下来。