Roles of Histone H3K27 demethylases in germ cell epigenetic development

描述(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(H3K27)甲基化是基因激活/抑制的全球调节因子，有助于跨细胞分裂的特定转录状态的表观遗传。成熟生殖系的建立以胚胎和成年生殖细胞发育过程中几个明确的表观遗传学变化为特征。我计划研究组蛋白H3K27去甲基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 H3K27去甲基酶在早期哺乳动物胚胎中是必需的，并将被证明是重新编程和分化事件的关键，这些事件对成熟配子的发育至关重要。为了验证这一假设，我的建议将利用小鼠遗传模型来评估H3K27去甲基酶在生殖细胞生物学中的全局和细胞特异性影响。虽然这些研究集中在生殖细胞发育上，但我的发现将揭示UTX和JmjdS在H3K27去甲基化中的体内功能，这些去甲基酶如何在哺乳动物生物发育中发挥作用，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发挥着重要作用，特别是以印记和表观遗传基因紊乱的形式(如Beckwith-Widemann、Prader-Willi、Angelmann和Rett综合征)或在全球范围内在癌症的大规模表观遗传学变化中发挥作用。H3K27甲基转移酶过表达调控前列腺癌细胞增殖，而H3K27三甲基化缺失与细胞衰老有关。了解H3K27去甲基酶如何调节生殖细胞谱系中的细胞命运决定，可能有助于理解癌症中调控不当的细胞分化事件的致癌本质。H3K27去甲基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.