Roles of Histone H3K27 demethylases in germ cell epigenetic development

描述（由申请人提供）：组蛋白翻译后修饰调节核小体结构，从而调节基因表达。组蛋白H3赖氨酸27（H3 K27）甲基化是基因激活/抑制的全局调节剂，并且有助于跨细胞分裂的限定转录状态的表观遗传。成熟生殖细胞系的建立以贯穿胚胎和成体生殖细胞发育的若干明确的表观遗传变化为特征。我计划研究组蛋白H3 K27去甲基化酶在生殖细胞发育生物学重大事件中的作用。我推测，Utx和JmjdS H3 K27脱甲基酶是必需的，在早期哺乳动物胚胎，并将证明是至关重要的重编程和分化事件的发展成熟配子。为了验证这一假设，我的提议将利用小鼠遗传模型来评估H3 K27脱甲基酶在生殖细胞生物学中的全局和细胞特异性影响。虽然这些研究的重点是生殖细胞发育，但我的研究结果将揭示Utx和JmjdS在H3 K27去甲基化中的体内功能，这些去甲基化酶如何在哺乳动物生物体发育中发挥作用，以及它们如何调节生殖细胞谱系中的干细胞分化/多能性。表观遗传学在人类疾病中起着重要作用，特别是在印记和表观遗传基因疾病（如Beckwith-Widemann，Prader-Willi，Angelmann和Rett综合征）的形式中或在癌症的大规模表观遗传变化中起着重要作用。H3 K27甲基转移酶的过表达调节前列腺癌中的细胞增殖，而H3 K27三甲基化的丧失与细胞衰老相关。了解H3 K27去甲基化酶如何调节生殖细胞谱系内的细胞命运决定，可能有助于了解癌症中失调的细胞分化事件的致癌性质。H3 K27去甲基化酶对这些目的的潜在治疗意义是无限的，但我们必须首先对它们如何调节细胞命运决定有一个基本的了解。

DESCRIPTION (provided by applicant): Histone posttranslational modifications regulate nucleosome structure and thus gene expression. Histone H3 Lysine 27 (H3K27) methylation is a global regulator of gene activation/repression and contributes to the epigenetic inheritance of defined transcriptional states across cell divisions. The establishment of a mature germline is characterized by several well-defined epigenetic changes throughout embryonic and adult germ cell development. I plan to study the role of Histone H3K27 demethylases in major events of germ cell developmental biology. I hypothesize that Utx and JmjdS H3K27 demethylases are required in the early mammalian embryo and will prove essential for reprogramming and differentiation events that are critical for development of mature gametes. To test this hypothesis, my proposal will utilize mouse genetic models to assess the global and cell specific impact of H3K27 demethylases in germ cell biology. While these studies focus on germ cell development, my findings will bring to light in vivo function of Utx and JmjdS in H3K27 demethylation, how these demethylases operate in mammalian organismal development, and how they regulate stem cell differentiation/pluripotency within the germ cell lineage. Epigenetics plays a major role in human disease, specifically in the form of imprinted and epigenetic gene disorders (such as Beckwith-Widemann, Prader-Willi, Angelmann, and Rett syndromes) or globally in large scale epigenetic changes of cancer. Overexpression of H3K27 methyl-transferases regulates cellular proliferation in prostate cancer, while loss of H3K27 trimethylation is associated with cellular senescence. Understanding how H3K27 demethylases regulate cell fate decisions within the germ cell lineage may be amendable to understanding the oncogenic nature of misregulated cellular differentiation events in cancer. The potential therapeautic implications of H3K27 demethylases towards these ends are limitless, but we must first have a basic understanding of how they regulate cellular fate decisions.