Regulation of human skin homeostasis by histone arginine methylation regulators

组蛋白精氨酸甲基化调节剂对人类皮肤稳态的调节

• 批准号: 8125807
• 负责人: Xiaomin Bao
• 金额: $ 5.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125807
• 关键词: Ablation; Acetylation; Adult; Animals; Arginine; Base Sequence; Calcium; Cell Cycle; Cessation of life; Chronic; DNA; Defect; Development; Differentiation Antigens; Differentiation and Growth; Disease; Enzymes; Epidermis; Epigenetic Process; Epithelial; Equilibrium; Evolution; Foundations; Funding; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Goals; Growth; Histone H4; Histones; Homeostasis; Human; Laboratories; Lysine; Malignant Neoplasms; Mediating; Methylation; Modeling; Mus; Neoplasms; Neoplastic Cell Transformation; Normal tissue morphology; Organ; Perinatal; Play; Process; Protein-Arginine N-Methyltransferase; Psoriasis; Regulation; Regulator Genes; Relative (related person); Role; Skin; Skin Tissue; Therapeutic; Tissue Differentiation; Tissue Model; Tissues; Training; Undifferentiated; base; design; genetic regulatory protein; histone methyltransferase; histone modification; human tissue; keratinocyte; keratinocyte differentiation; overexpression; skin disorder; small hairpin RNA; tissue regeneration; treatment strategy; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：表皮稳态在包括牛皮癣，慢性伤口和癌症在内的许多人皮肤疾病中受到破坏。对表观遗传调节剂的表皮生长和分化的基因调节控制，特别是组蛋白精氨酸甲基转移酶PRMT1和组蛋白精氨酸脱甲基酶JMJD6的理解是该训练计划的主要重点。 首先，我们将定义组蛋白精氨酸脱甲基酶JMJD6的作用，该脱甲基脱甲基在表皮稳态中脱甲基H4精氨酸3二甲基化（H4R3ME2）。在我们的初步研究中，我们观察到在人角质形成细胞分化过程中，组蛋白标记H4R3ME2受动态调节。在培养的原代人角质形成细胞中，H4R3ME2组蛋白精氨酸脱甲基酶JMJD6的丧失会损害钙诱导的分化。为了扩展这些发现，我们将定义JMJD6在完整组织水平上正常人表皮组织稳态中的作用，利用我们实验室中建立的人体组织再生模型。我们还将表征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（甲基甲基甲基H4R3）在早期朝向表皮肿瘤中的作用。我们最近观察到需要PRMT1抑制表皮分化。通过多个经过验证的短发RNA（SHRNA）损失PRMT1可抑制增殖并诱导分化标记基因表达。此外，PRMT1在多个人类癌组织中过表达。由于肿瘤演化的第一步的特征是生长和分化的改变，因此我们假设PRMT1是组织进展向肿瘤所必需的。因此，我们将定义PRMT1在经历肿瘤转化的表皮中的作用。 在拟议的资金期结束时，我们希望将JMJD6和PRMT1基因调节蛋白在控制表皮增殖和分化方面的机械作用表征，以此为未来开发的疗法的基础。 公共卫生相关性：表皮增殖和分化受到精确的空间和时间控制，以达到正常的皮肤稳态，这种平衡在各种常见的人类皮肤疾病中受到破坏，包括牛皮癣，慢性伤口和癌症。表观遗传调节剂，例如修饰酶的组蛋白，通过通过多个细胞分裂循环控制基因表达而不改变DNA核苷酸序列，在这些过程中起关键作用。为了利用我们实验室中建立的人体组织模型的强度，特别是人类表皮组织再生模型和人类皮肤组织肿瘤模型的强度，该训练计划旨在理解表观遗传调节剂的基因调节机制，该机制通过表观遗传调节剂，为人类表皮细胞提供治疗信息，以提供人类表皮分层的治疗信息。