DNA methylation regulation through the UHRF1 oncoprotein

通过 UHRF1 癌蛋白调节 DNA 甲基化

基本信息

批准号：
10015243
负责人：
Robert Mark Vaughan
金额：
$ 4.45万
依托单位：
VAN ANDEL INSTITUTE GRADUATE SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-09 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015243
关键词：
Aberrant DNA Methylation Acetylesterase Affect Area Basic Science Binding Biochemical Biochemistry Biological Biological Models Biophysics CRISPR/Cas technology Cancer Model Cancerous Cell Differentiation process Cell Proliferation Cellular biology Chromatin Clinical Colorectal Cancer Complement DNA DNA Binding DNA Ligases DNA Maintenance DNA Methylation DNA Methylation Regulation DNA Modification Methylases DNA biosynthesis Data Data Analyses Development Disease Drug Targeting Elements Embryonic Development Enzymatic Biochemistry Epigenetic Process Fellowship Fibrinogen Gene Expression Gene Expression Regulation Gene Silencing Genetic Transcription Genetic study Genomic Instability Genomics Goals Health Histone H3 Histones Homologous Gene Human In Vitro Intestinal Cancer Intestines Investments Ligase Link Linker DNA Maintenance Malignant Neoplasms Messenger RNA Metabolism Methyltransferase Modeling Molecular Neoplasm Metastasis Okazaki fragments Oncogenic Oncoproteins Organoids PHD Finger Pathogenicity Pathologic Pattern Phase Process Protein Biochemistry Proteins Regulator Genes Research Research Project Grants Research Training Ring Finger Domain Role Shapes Signal Transduction Structure Techniques Technology Therapeutic Training Tumor Suppressor Genes Ubiquitin Up-Regulation Work anticancer research bacterial resistance base blastomere structure cancer cell cancer therapy cancer type career epigenome epigenomics genome editing in vivo inhibitor/antagonist insight interest methylation pattern microbial microbiome microbiome research microorganism mouse model next generation sequencing novel precision medicine protein function recruit response screening structural biology therapeutic target tumor tumor progression ubiquitin-protein ligase undergraduate research

项目摘要

PROJECT SUMMARY DNA methylation is a key epigenetic regulator of gene expression and is essential for embryonic development and cell differentiation. Aberrant DNA methylation patterning, a hallmark of nearly all human cancers, is a major contributor to tumor suppressor gene silencing and genomic instability that promotes cancer development and progression. The epigenetic oncoprotein UHRF1 is intimately linked to the control of DNA methylation through recruitment of the maintenance DNA methyltransferase DNMT1 to replicating chromatin. UHRF1 is frequently upregulated in human cancers and its depletion in model systems has demonstrated tumor suppressive effects. These studies have motivated intense recent analysis of UHRF1 biological/pathological function and have sparked clinical interest in the development of UHRF1 inhibitors for cancer therapy. A recently described interaction between UHRF1 and DNA ligase 1 (LIG1) established LIG1 as a novel regulator of DNA methylation and presents a potentially exploitable chromatin-targeting mechanism for UHRF1. The overall goal of the F99 phase of this fellowship is to determine the role of LIG1 in UHRF1 molecular and oncogenic functions. Specifically, the Aims are 1a) to determine the role of LIG1 in DNA methylation maintenance and 1b) evaluate the therapeutic potential of disrupting the UHRF1-LIG1 interaction. The training objectives of the F99 phase include building expertise in technologies of CRISPR/Cas9 genome editing, genomic and epigenomic data analysis, and cancer cell biology. The K00 phase of this fellowship (Aim 2), will define the impact of microorganisms and their metabolites on epigenetic signaling in colorectal cancer. Intestinal organoids and mouse models of intestinal cancer will be used to determine if the gut microfloral metabolism elicits transcriptional responses in host cancer cells. Data and training acquired in this phase will focus my trajectory toward leading an interdisciplinary cancer research lab studying the symbiotic and pathogenic relationship between the microbiome and host epigenome in human health and cancer.

项目摘要 DNA甲基化是基因表达的关键表观遗传调节剂，对于胚胎发育至关重要和细胞分化。异常的DNA甲基化模式，几乎所有人类癌的标志是主要的促进癌症发展的肿瘤抑制基因沉默和基因组不稳定性的贡献者进展。表观遗传学癌蛋白UHRF1与通过DNA甲基化的控制密切相关募集维持DNA甲基转移酶DNMT1复制染色质。 UHRF1经常在人类癌症中上调及其在模型系统中的耗竭表现出肿瘤抑制作用。这些研究激发了对UHRF1生物学/病理功能的最近分析，并具有对癌症治疗的UHRF1抑制剂的发展引发了临床兴趣。最近描述的UHRF1和DNA连接酶1（LIG1）之间的相互作用将Lig1建立为一种新颖 DNA甲基化的调节剂并提出了UHRF1的潜在可剥削的染色质靶向机制。该研究金的F99阶段的总体目标是确定Lig1在UHRF1分子和致癌功能。具体而言，目的是1A）确定LIG1在DNA甲基化维持中的作用和1B）评估破坏UHRF1-LIG1相互作用的治疗潜力。培训目标 F99阶段包括在CRISPR/CAS9基因组编辑，基因组和基因组技术技术方面的建立专业知识表观基因组数据分析和癌细胞生物学。该研究金的K00阶段（AIM 2）将定义微生物及其代谢物对大肠癌表观遗传信号传导的影响。肠癌肠癌的小鼠模型将用于确定肠道菌核代谢是否引起宿主癌细胞中的转录反应。在此阶段获得的数据和培训将集中于我的轨迹朝着研究共生和致病关系的跨学科癌症研究实验室在人类健康和癌症中的微生物组和宿主表观基因组之间。