Epigenetic enhancer control in maintaining homeostasis and preventing carcinogenesis in the epidermis

项目摘要 表观遗传学影响细胞生理学的所有领域，表观遗传失调在人类中普遍存在， 疾病鉴于表观遗传变化固有的可逆性，这为遗传学研究提供了一个很好的机会。 鉴于最近表观基因组修饰药物的快速发展，发现新的治疗方法。有趣的是， 大规模的人类测序工作已经揭示了被太阳晒坏但临床上其他方面正常的人类 皮肤，可以在表观遗传染色质修饰酶中隐藏频繁的突变。这些突变包括 通常在皮肤鳞状细胞癌（cSCC）中观察到， 人类恶性肿瘤，以及重大的经济和公共卫生负担。最近的数据显示， 表观遗传突变可能是表皮恶性克隆形成的重要驱动因素， 假设适当的表观遗传功能是维持表皮稳态和 防止致癌作用的开始。值得注意的是，尽管这两种突变的发生率很高， 表观遗传修饰剂和cSCC，通过破坏染色质修饰的精确机制， 驱动cSCC起始的酶实际上是未知的。在本提案中，我们将利用多种模式 包括人类患者样品和各种转基因小鼠模型的系统，与几种 创新的全基因组和功能性技术，以确定 染色质调节、转录、表皮细胞命运和表皮癌发生的起始。 总的来说，这些研究有望为表观遗传疗法的开发和利用提供信息， 未来

PROJECT ABSTRACT Epigenetics impacts all areas of cellular physiology, and epigenetic dysregulation is pervasive in human disease. Given the inherent reversibility of epigenetic changes, this presents a great opportunity for the discovery of novel therapeutics given the recent rapid development of epigenome-modifying drugs. Intriguingly, large-scale human sequencing efforts have revealed that sun-damaged, but clinically otherwise normal human skin, can harbor frequent mutations in epigenetic chromatin modifying enzymes. These include mutations that have been typically observed in cutaneous squamous cell carcinoma (cSCC), the second most common of all human malignancies, and a major economic and public health burden. Recent data suggests that these epigenetic mutations may be important drivers of malignant clone formation in the epidermis, provoking the hypothesis that proper epigenetic function is required for both maintaining epidermal homeostasis and preventing the initiation of carcinogenesis. Remarkably, despite the high incidence of both these mutations in epigenetic modifiers and cSCC, the precise mechanisms by which disruption of chromatin modifying enzymes drives the initiation of cSCC are virtually unknown. In this proposal, we will utilize multiple model systems including human patient samples and a variety of transgenic mouse models, combined with several innovative genome-wide and functional technologies in order to define the mechanistic links between chromatin regulation, transcription, epidermal cell fate, and the initiation of epidermal carcinogenesis. Collectively, these studies promise to inform both the development and utilization of epigenetic therapies in the future.