Epigenetic Regulators in Epidermal Homeostasis and Neoplasia

描述（由申请人提供）：我的长期目标是指导一个富有成效的研究实验室，教授学生和研究员，同时对上皮生物学做出重大贡献。特别是，我对细胞如何分化成不同的发育谱系并保持细胞记忆感兴趣。我对表皮作为一个模型系统很感兴趣，因为皮肤具有恒定的周转率，具有增殖和分化的周期。这些循环必须严格控制，否则就会迅速出现紊乱。我也对这些基本过程的失调如何导致癌症等人类疾病感兴趣。这个培训计划将帮助我实现这些目标，因为我将学习解决计划中的问题的所有技术和技能。具体来说，在这个奖项期间的培训将使我在上皮生物学、体内哺乳动物模型系统、基因组学和癌症生物学方面获得新的专业知识。我的近期目标是实现以下所述的提案的目标。表皮稳态是一个受到严格调控的过程，开始于活跃的细胞分裂，最终分化成无核角质细胞，形成皮肤的不渗水层。在生长和分化之间的平衡的扰动可导致各种各样的人类皮肤疾病。增殖增加和分化减少可导致增生性疾病，如牛皮癣、基底细胞癌或鳞状细胞癌。因此，全面了解表皮生长和分化的调节因子将是解开皮肤疾病分子机制的关键，这可能会导致针对皮肤疾病的靶向指导疗法的发展。这项工作旨在确定表观遗传修饰因子在表皮生长、分化和肿瘤发生中的作用。我们之前的研究结果表明，组蛋白去甲基化酶JMJD3通过去除H3K27me3标记的表皮分化基因启动子上的甲基标记来控制表皮分化。由于JMJD3在表皮分化中的核心作用，JMJD3的功能改变可能导致肿瘤的发生。目的描述JMDJ3在人表皮肿瘤进展中的作用。为了寻找其他与表皮生长和分化有关的表观遗传修饰因子，我们系统地去除DNA和组蛋白修饰酶的功能，发现DNA甲基转移酶1 （DNMT1）和组蛋白去乙酰化酶2 （HDAC2）对表皮生长和分化有影响。Aim II主要研究DNMT1和HDAC2在表皮生长、分化和肿瘤形成中的作用。

DESCRIPTION (provided by applicant): My long-term goal is to spend a career guiding a productive research laboratory teaching students and fellows while making significant contributions to epithelial biology. In particular, I am interested in how cells differentiate into different developmental lineages and retain that cellular memory. I am interested in the epidermis as a model system since the skin has a constant turnover rate with cycles of proliferation and differentiation. These cycles must be tightly regulated or disorders would rapidly arise. I am also interested in how dysregulation of these fundamental processes can lead to human diseases such as cancer. This training proposal will help me attain these goals because of all the techniques and skills I will learn to address the questions of the proposal. Specifically, the training during this award period will provide me with new expertise in epithelial biology, in vivo mammalian model systems, genomics, and cancer biology. My immediate goal is to accomplish the aims of the proposal as described below. Epidermal homeostasis is a tightly regulated process that begins with actively dividing cells that eventually differentiate into enucleated corneocytes that form the water-impermeable layer of the skin. Perturbations in the balance between growth and differentiation can lead to a variety of human skin disorders. Increased proliferation and diminished differentiation can lead to hyperproliferative disorders such as psoriasis, basal or squamous cell carcinomas. Thus, a comprehensive understanding of the regulators of epidermal growth and differentiation would be key to unlocking the molecular mechanisms underlying skin disorders which could potentially lead to the development of target guided therapies for skin disorders. This effort aims to define the role of epigenetic modifiers in epidermal growth, differentiation, and neoplasia. Our previous findings demonstrated that the histone demethylase, JMJD3, controls epidermal differentiation by removal of methyl marks on H3K27me3 marked epidermal differentiation gene promoters. Because of the central role of JMJD3 in epidermal differentiation, functional alterations in JMJD3 may contribute to neoplasia. Aim I will characterize the role of JMDJ3 in human epidermal tumor progression. In order to identify other epigenetic modifiers with a role in epidermal growth and differentiation, we systematically depleted the function of DNA and histone modifying enzymes and found DNA methyltransferase 1 (DNMT1) and Histone deacetylase 2 (HDAC2) to have effects on epidermal growth and differentiation. Aim II focuses on characterizing the role of DNMT1 and HDAC2 on epidermal growth, differentiation and neoplasia.