Regulation of human skin homeostasis by histone arginine methylation regulators

描述(申请人提供)：表皮动态平衡在许多人类皮肤病中被破坏，包括牛皮癣、慢性伤口和癌症。通过表观遗传调节，特别是组蛋白精氨酸甲基转移酶PRMT1和组蛋白精氨酸去甲基酶JMJD6，增加对表皮生长和分化的基因调控的了解，是本培训计划的中心重点。首先，我们将确定组蛋白精氨酸去甲基酶JMJD6，它使组蛋白H4精氨酸3二甲基化(H4R3me2)去甲基化，在表皮动态平衡中的作用。在我们的初步研究中，我们观察到组蛋白标记H4R3me2在人类角质形成细胞分化过程中受到动态调节。在原代培养的人角质形成细胞中，H4R3me2组蛋白精氨酸去甲基酶JMJD6的缺失会削弱钙诱导的分化。为了扩展这些发现，我们将利用我们实验室建立的人类组织再生模型，在完整组织水平上定义JMJD6在正常人类表皮组织动态平衡中的作用。我们还将研究JMJD6在表皮生长和分化中的作用。其次，我们将阐明组蛋白精氨酸甲基转移酶PRMT1，其甲基化组蛋白H4R3，在早期进展为表皮肿瘤中的作用。我们最近观察到PRMT1是抑制表皮分化所必需的。多个有效的短发夹状RNA(ShRNAs)缺失PRMT1可抑制细胞增殖并诱导分化标记基因的表达。此外，PRMT1在多种人类肿瘤组织中过表达。由于肿瘤进化的第一步以生长和分化的改变为特征，我们假设PRMT1是组织向肿瘤进展所必需的。因此，我们将确定PRMT1在经历肿瘤转化的表皮中的作用。在拟议的资助期结束时，我们希望能够表征JMJD6和PRMT1基因调控蛋白在控制表皮增殖和分化中的机制作用，为未来开发以表皮动态平衡被破坏为特征的人类疾病的新治疗策略奠定基础。 与公共健康相关：表皮的增殖和分化受到精确的空间和时间控制，以实现正常的皮肤动态平衡，这种平衡在包括牛皮癣、慢性伤口和癌症在内的一系列常见人类皮肤病中被破坏。表观遗传调节因子，如组蛋白修饰酶，通过在不改变DNA核苷酸序列的情况下，通过多个细胞分裂周期控制基因表达，在这些过程中发挥关键作用。利用我们实验室建立的人体组织模型，特别是正常人类表皮组织再生模型和人类皮肤组织肿瘤模型，本培训计划旨在了解表观遗传调节因子调控表皮动态平衡的基因调控机制，为人类上皮疾病提供治疗信息。

DESCRIPTION (provided by applicant): Epidermal homeostasis is disrupted in a host of human skin diseases, including psoriasis, chronic wounds, and cancer. Increased understanding of the gene regulatory control of epidermal growth and differentiation by epigenetic regulators, specifically histone arginine methyltransferase PRMT1 and histone arginine demethylase JMJD6, is the central focus of this training plan. First, we will define the role of the histone arginine demethylase JMJD6, which demethylates histone H4 Arginine 3 dimethylation (H4R3me2), in epidermal homeostasis. In our preliminary studies, we observed that the histone mark H4R3me2 is dynamically regulated during human keratinocyte differentiation. In cultured primary human keratinocytes, loss of the H4R3me2 histone arginine demethylase JMJD6 impairs calcium- induced differentiation. To extend these findings, we will define the role of JMJD6 in normal human epidermal tissue homeostasis at the level of intact tissue, leveraging the human tissue regeneration models established in our laboratory. We will also characterize the action of JMJD6 in epidermal growth and differentiation. Second, we will elucidate the role of the histone arginine methyltransferase PRMT1, which methylates histone H4R3, in early progression towards epidermal neoplasia. We recently observed that PRMT1 is required to suppress epidermal differentiation. Loss of PRMT1 by multiple validated short-hairpin RNAs (shRNAs) inhibits proliferation and induces differentiation marker gene expression. Furthermore, PRMT1 is overexpressed in multiple human cancer tissues. Since the first steps in tumor evolution is characterized by alterations in growth and differentiation, we hypothesize that PRMT1 is required for tissue progression toward neoplasia. We will therefore define the role of PRMT1 in epidermis undergoing neoplastic transformation. At the end of the proposed funding period, we hope to have characterized the mechanistic actions of both JMJD6 and PRMT1 gene regulatory proteins in the control of epidermal proliferation and differentiation as a foundation for the future development of new treatment strategies for human disorders of characterized by disrupted epidermal homeostasis. PUBLIC HEALTH RELEVANCE: Epidermal proliferation and differentiation are subject to precise spatial and temporal control to achieve normal skin homeostasis, a balance that is disrupted in a wide spectrum of common human skin diseases including psoriasis, chronic wounds and cancer. Epigenetic regulators, such as histone modifying enzymes, play critical roles in these processes by controlling gene expression through multiple cell division cycles without altering DNA nucleotide sequence. Leveraging the strength of human tissue models established in our laboratory, specifically the normal human epidermal tissue regeneration model and the human skin tissue neoplasm model, this training plan is directed at understanding the gene regulatory mechanisms governing epidermal homeostasis by epigenetic regulators, providing therapeutic information for human epithelial disorders.