DNA methylation regulation through the UHRF1 oncoprotein

通过 UHRF1 癌蛋白调节 DNA 甲基化

• 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
• 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

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因子，对胚胎发育至关重要 和细胞分化。异常的DNA甲基化模式是几乎所有人类癌症的标志， 肿瘤抑制基因沉默和基因组不稳定性的贡献者，促进癌症的发展， 进展表观遗传癌蛋白UHRF 1与DNA甲基化的控制密切相关， 维持DNA甲基转移酶DNMT 1向复制染色质的募集。UHRF 1通常 在人类癌症中上调，并且在模型系统中耗尽，已经证明了肿瘤抑制作用。 这些研究激发了最近对UHRF 1生物/病理功能的深入分析， 引发了对开发用于癌症治疗的UHRF 1抑制剂的临床兴趣。 最近描述的UHRF 1和DNA连接酶1（LIG 1）之间的相互作用确立了LIG 1作为一种新的DNA连接酶。 调节DNA甲基化，并提出了一个潜在的利用染色质靶向机制UHRF 1。 本研究F99阶段的总体目标是确定LIG 1在UHRF 1分子和细胞中的作用。 致癌功能具体而言，目的是1a）确定LIG 1在DNA甲基化维持中的作用 和1b）评估破坏UHRF 1-LIG 1相互作用的治疗潜力。的培养目标 F99阶段包括建立CRISPR/Cas9基因组编辑、基因组和 表观基因组数据分析和癌细胞生物学。该奖学金的K 00阶段（目标2）将定义 微生物及其代谢产物对结直肠癌表观遗传信号传导的影响。肠类器官 和小鼠肠癌模型将用于确定肠道微生物代谢是否会促进 在宿主癌细胞中的转录反应。在这个阶段获得的数据和训练将集中我的轨迹 领导一个跨学科的癌症研究实验室，研究共生和致病的关系， 微生物组和宿主表观基因组在人类健康和癌症中的关系。