Epigenetic profiling in Utx germline conditional knockouts and F1 offspring

Susceptibility to cancer is highly heritable, but much of this heritability remains unexplained. Some "missing" cancer heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. These data describe the finding that deletion of the chromatin regulator Utx (Kdm6a) in the mouse male germ line results in an elevated tumor incidence in genetically wild type offspring. This effect increases following passage through two successive generations of Utx male germline deletion, but is lost following passage through a wild type germ line. We find widespread redistribution of the H3K27me3 mark in Utx mutant germ cells, and further define approximately 200 regions marked by H3K27me3 that exhibit increased DNA methylation, both in sperm of Utx mutants and in somatic tissue of their progeny. These hypermethylated regions are located in functional enhancers and may alter regulation of genes involved in cancer initiation or progression. The results indicate that epigenetic changes in the male germ line can profoundly impact cancer susceptibility in adult offspring. ChIP-seq, RRBS, and RNA-seq in cKO sperm and spermatids and in offspring bone marrow. ChIP-seq control spermatids.

癌症易感性具有高度可遗传性，但目前仍有大量该类可遗传性尚未得到阐明。部分“缺失”的癌症可遗传性，可能由亲本生殖系的表观遗传变化介导——此类变化并不涉及亲代向子代传递遗传变异体。本数据集所收录的数据对应一项研究发现：在小鼠雄性生殖系中敲除染色质调控因子Utx（Kdm6a），会使遗传背景为野生型的子代小鼠肿瘤发生率升高。该效应在经过两代连续的Utx雄性生殖系敲除后会进一步增强，但在经过野生型生殖系传递后则会消失。研究团队发现，Utx突变生殖细胞中H3K27me3标记物出现广泛的重分布；并进一步确定了约200个带有H3K27me3标记的区域，这些区域在Utx突变小鼠的精子以及其子代的体细胞组织中均呈现DNA甲基化水平升高的特征。这些高甲基化区域位于功能性增强子中，可能会改变与癌症起始或进展相关基因的调控模式。研究结果表明，雄性生殖系中的表观遗传变化可对成年子代的癌症易感性产生深远影响。本数据集包含cKO小鼠精子及精子细胞、子代骨髓中的ChIP-seq、RRBS及RNA-seq数据，以及ChIP-seq对照精子细胞数据。