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

表观遗传增强子控制维持稳态和预防表皮癌变

基本信息

批准号：
10866006
负责人：
Brian Capell
金额：
$ 6.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10866006
关键词：
Actinic keratosis Aging Area Biological Models Cell Count Cell physiology Cells ChIP-seq Chromatin Chromatin Remodeling Factor Clinical Data Development Disease Economic Burden Economics Enhancers Enzymes Epidermis Epigenetic Process Epithelium Functional disorder Future Gene Expression Regulation Genes Genetic Genetic Transcription Histone H3 Homeostasis Human In Vitro Incidence Individual KDM1A gene Keratin Knock-in Link Lysine Maintenance Malignant - descriptor Malignant Neoplasms Mediating Methylation Modeling Mus Mutation Neoplasms Patients Persons Pharmaceutical Preparations Phenotype Population Prevention strategy Preventive Process Proliferating Public Health Regulation Reporting Repression Role Sampling Skin Skin Cancer Technology Testing Therapeutic Transgenic Mice cancer initiation carcinogenesis chemical carcinogenesis data integration dimethylbenzanthracene epigenetic therapy epigenome epigenome editing genome-wide histone demethylase histone methylation histone methyltransferase histone modification human disease human model in vivo innovation loss of function melanoma mouse model novel therapeutics overexpression pharmacologic premalignant prevent restoration skin barrier skin disorder skin squamous cell carcinoma sun damage transcription factor transcriptome sequencing virtual

项目摘要

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.

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，这为鉴于最近表观基因组修饰药物的快速发展，新疗法的发现。有趣的是，大规模的人类测序工作表明，受阳光损伤但临床其他方面正常的人类皮肤，可能含有表观遗传染色质修饰酶的频繁突变。这些包括突变通常在皮肤鳞状细胞癌 (cSCC) 中观察到，这是第二常见的人类恶性肿瘤，以及重大的经济和公共卫生负担。最近的数据表明，这些表观遗传突变可能是表皮恶性克隆形成的重要驱动因素，引发假设认为维持表皮稳态和维持表皮稳态都需要适当的表观遗传功能防止癌变的发生。值得注意的是，尽管这两种突变在表观遗传修饰剂和 cSCC，破坏染色质修饰的精确机制驱动 cSCC 发生的酶几乎是未知的。在这个提案中，我们将利用多个模型系统包括人类患者样本和各种转基因小鼠模型，并结合了多种创新的全基因组和功能技术，以确定之间的机械联系染色质调节、转录、表皮细胞命运和表皮癌变的起始。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。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

From Enhancers to Keratinocyte Cancers.

DOI：
10.1016/j.jid.2020.11.008
发表时间：
2021-05
期刊：
The Journal of investigative dermatology
影响因子：
0
作者：
Capell BC
通讯作者：
Capell BC

Loss of TET2 Tips the Scales Toward Tumorigenesis.

DOI：
10.1016/j.jid.2021.11.023
发表时间：
2022-05
期刊：
JOURNAL OF INVESTIGATIVE DERMATOLOGY
影响因子：
6.5
作者：
Capell, Brian C.
通讯作者：
Capell, Brian C.

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease.

DOI：
10.1172/jci.insight.170739
发表时间：
2023-09-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Zaver, Shivam A.;Sarkar, Mrinal K.;Egolf, Shaun;Zou, Jonathan;Tiwaa, Afua;Capell, Brian C.;Gudjonsson, Johann E.;Simpson, Cory L.
通讯作者：
Simpson, Cory L.

Molecular Mechanisms of Cutaneous Squamous Cell Carcinoma.

皮肤鳞状细胞癌的分子机制。

DOI：
10.3390/ijms23073478
发表时间：
2022-03-23
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Hedberg ML;Berry CT;Moshiri AS;Xiang Y;Yeh CJ;Attilasoy C;Capell BC;Seykora JT
通讯作者：
Seykora JT

MLL4 mediates differentiation and tumor suppression through ferroptosis.

DOI：
10.1126/sciadv.abj9141
发表时间：
2021-12-10
期刊：
Science advances
影响因子：
13.6
作者：
Egolf S;Zou J;Anderson A;Simpson CL;Aubert Y;Prouty S;Ge K;Seykora JT;Capell BC
通讯作者：
Capell BC