Elucidating the role of REST in shaping the epigenome of melanoma

阐明 REST 在塑造黑色素瘤表观基因组中的作用

基本信息

批准号：
10643815
负责人：
Christie Bao Thu Nguyen
金额：
$ 5.27万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2020-06-18 至 2024-06-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10643815
关键词：
Address Apoptosis Architecture Automobile Driving BRAF gene Binding Biological Assay Cadherins Cell Cycle Cell Cycle Arrest Cell Line Cell physiology Cells Cessation of life Chromatin Complex Coupled DNA DNA Binding Data Dependence Development Diagnosis Disease Distant Elements Enhancers Epigenetic Process Excision Exhibits Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Genetic Transcription Genomic approach Genomics Growth High-Throughput Nucleotide Sequencing Histones Human Immunotherapy Impairment Incidence Investigation Laboratories Learning MEKs Malignant Neoplasms Mediating Melanoma Cell Metastatic Melanoma Molecular Neural Crest Cell Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neuroglia Neurons Organ Pathway interactions Patients Pattern Phenotype Play Post-Translational Protein Processing Proliferating Reader Refractory Disease Regulatory Element Relapse Repression Research Role Seminal Shapes Skin Cancer Survival Rate Testing The Cancer Genome Atlas Therapeutic Time Toxic effect Transcriptional Activation Transposase United States Up-Regulation Variant WNT Signaling Pathway Writing Zinc Fingers chromatin immunoprecipitation cofactor epigenome falls gain of function gene repression inhibitor interest knock-down loss of function lymph nodes melanocyte melanoma member migration mutant new therapeutic target novel therapeutic intervention overexpression p38 Mitogen Activated Protein Kinase patient subsets pharmacologic programs promoter recruit relapse patients response targeted treatment transcription factor transcriptome sequencing transcriptomics tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY Melanoma is the most aggressive form of skin cancer with rising incidence. Despite significant advances, available therapies are effective only in distinct subsets of patients where relapse, treatment-refractory disease, and/or significant toxicities commonly occur. It has become increasingly evident that epigenetic alterations that lead to aberrant gene expression programs play an integral role in melanoma initiation and development. Repressor Element-1 (RE-1) Silencing Transcription (REST), a zinc ﬁnger transcription factor (TF), has been implicated in a diverse subset of cancers as pro-proliferative in neural tumors and anti-proliferative in non-neural tumors. REST binds DNA in a sequence-specific manner at RE1 motifs and primarily functions to repress neuronal gene transcription in non-neuronal cells. REST-mediated gene repression is achieved by the recruitment of several chromatin modifying complexes to DNA that erase active histone marks and write repressive marks. Relevant to my proposal, TCGA data indicates that REST is overexpressed in metastatic melanoma compared to primary melanoma. Yet to date, there are no studies that have explored REST in regulating aberrant gene expression programs in melanoma. I found that REST loss-of-function impairs melanoma proliferation by inducing cell cycle arrest and subsequent apoptosis. RNA-sequencing analysis upon REST knockdown revealed that REST regulates key melanoma survival genes, enriched in pathways related to Cadherin, p38, and Wnt Signaling. Together, my phenotypic and transcriptomic analysis of REST depletion demonstrated, for the first time, that melanoma cells are dependent on REST. In this proposal, I seek to continue to test my hypothesis that through the modulation of the epigenetic landscape, REST regulates pro-tumorigenic transcriptional programs in melanoma, utilizing a combination of functional and genomic approaches. I expect my findings to open avenues for investigation into the molecular mechanisms and cellular functions of REST and ultimately, to present a novel therapeutic strategy for melanoma patients.

项目摘要黑色素瘤是皮肤癌最具侵略性的形式，并发生了增加的事件。尽管取得了重大进展，可用疗法仅在救济，治疗难治性疾病的患者的不同子集中有效和/或大量毒性通常发生。越来越多的证据表明，表观遗传改变导致异常基因表达程序在黑色素瘤倡议和发展中起着不可或缺的作用。阻遏物元素1（RE-1）沉默转录（REST）（锌纤维转录因子（TF））已经是在癌症的潜水员子集中实施，以促进神经肿瘤的促销并在非神经肿瘤中进行抗增殖肿瘤。 REST以RE1基序以序列特异性的方式结合DNA，并与副本结合非神经元细胞中的神经元基因转录。静止介导的基因表达是通过募集几种染色质修饰复合物中的DNA，以擦除活性组蛋白标记并编写压抑标记。与我的建议相关，TCGA数据表明静止在转移性中过表达黑色素瘤与原发性黑色素瘤相比。迄今为止，尚无研究探索的休息调节黑色素瘤中异常基因表达程序。我发现休息的功能障碍会损害通过诱导细胞周期停滞和随后的细胞凋亡，黑色素瘤增殖。 RNA测序分析休息敲低表明，REST调节关键的黑色素瘤生存基因，富含与 Cadherin，P38和Wnt信号传导。共同对休息部署的表型和转录组分析在一起首次证明黑色素瘤细胞取决于静止。在此提案中，我试图继续为了测试我的假设，即通过调节表观遗传景观，REST调节促肿瘤型黑色素瘤中的转录程序，结合了功能和基因组方法。我希望我的发现是为了投资于分子机制和静止和细胞功能的途径最终，为黑色素瘤患者提出一种新的治疗策略。