DNA methylation regulation through the UHRF1 oncoprotein

项目总结 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，是一种主要的 肿瘤抑制基因沉默和基因组不稳定的贡献者，促进癌症的发展和 进步。表观癌蛋白uhrf1与dna甲基化的控制密切相关。 将维持DNA甲基转移酶DNMT1重新招募到复制染色质。Uhrf1经常 在人类癌症中上调，在模型系统中它的缺失已经证明了肿瘤抑制作用。 这些研究推动了最近对uhrf1生物/病理功能的密集分析，并 激发了临床对开发用于癌症治疗的uhrf1抑制剂的兴趣。 最近描述的uhrf1和DNA连接酶1(LIG1)之间的相互作用使LIG1成为一种新的 DNA甲基化的调节者，并提出了一种潜在的可开发的uhrf1染色质靶向机制。 这项研究的F99阶段的总体目标是确定LIG1在uhrf1分子和 致癌功能。具体地说，目的是1)确定LIG1在DNA甲基化维持中的作用 以及1b)评估干扰uhrf1-LIG1相互作用的治疗潜力。的培训目标 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K00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的影响。肠道类器官 小鼠的肠癌模型将被用来确定肠道微花代谢是否会引发 宿主癌细胞的转录反应。在这个阶段获得的数据和培训将集中在我的职业发展轨迹上 走向领导一个研究共生与致病关系的跨学科癌症研究实验室 微生物组和宿主表观基因组与人类健康和癌症之间的关系。

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.