Epigenetic Regulators in Epidermal Homeostasis and Neoplasia

描述(由申请者提供)：我的长期目标是在指导一家富有成效的研究实验室教授学生和研究员的同时，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，因为皮肤有一个恒定的周转率，伴随着增殖和分化的周期。这些周期必须受到严格监管，否则将迅速出现混乱。我还对这些基本过程的失调如何导致癌症等人类疾病感兴趣。这个培训方案将帮助我实现这些目标，因为我将学习所有的技巧和技能来解决方案中的问题。具体地说，此次获奖期间的培训将使我在上皮生物学、活体哺乳动物模型系统、基因组学和癌症生物学方面获得新的专业知识。我的直接目标是实现提案的目标，如下所述。表皮动态平衡是一个严格调控的过程，从积极分裂细胞开始，这些细胞最终分化为去核的角质细胞，形成皮肤的不透水层。生长和分化之间的平衡失调可能会导致各种人类皮肤疾病。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控因素将是解开皮肤病潜在分子机制的关键，这可能会导致皮肤病靶向治疗的发展。这项工作旨在确定表观遗传修饰物在表皮生长、分化和肿瘤形成中的作用。我们以前的发现表明，组蛋白去甲基酶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在表皮分化中的中心作用，JMJD3的功能改变可能有助于肿瘤的发生。目的研究JMDJ3在人表皮肿瘤发生发展中的作用。为了寻找其他在表皮生长和分化中起作用的表观遗传修饰因子，我们系统地去除了DNA和组蛋白修饰酶的功能，发现DNA甲基转移酶1(DNMT1)和组蛋白脱乙酰基酶2(HDAC2)对表皮生长和分化有影响。目的研究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.