1998 — 2016 |
Vertino, Paula M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genesis and Consequences of Aberrant Dna Methylation
DESCRIPTION (provided by applicant): Our overall research initiative is focused on understanding the molecular basis of aberrant DNA methylation and its role in human carcinogenesis. Gene silencing associated with the aberrant methylation of promoter region CpG islands is a common epigenetic alteration that contributes to the inactivation of tumor suppressor and other genes in human cancers. At present, there is little known about how or why particular genes succumb to this aberrant event, and the mechanisms in which an active gene progresses to a methylated and inactive state are not well understood. Emerging evidence linking DNA methylation with posttranslational modification of histones suggests that the local chromatin architecture may be a critical determinant of normal, and abnormal, DNA methylation patterning. We propose that the aberrant methylation arises from a failure in cis of a mechanism that blocks or actively opposes the spread of heterochromatin. The goal of this renewal application is to further explore the idea that CpG islands define a distinct domain at the level of chromatin, and that the integrity of this domain prevents aberrant methylation in normal cells. Our studies will focus on a novel gene identified in our laboratory, TMS1, that is silenced by epigenetic means in human breast and other cancers. Specifically, we plan to determine whether DNAsel hypersentitive sites identified at the boundary between the unmethylated CpG island and methylated flanking DNA act in cis to protect the CpG island from de novo methylation and the influences of surrounding chromatin. Secondly, we will characterize a novel methylation-sensitive complex that binds to the TMS1 CpG island in its unmethylated state. Finally, we will test the hypothesis that aberrant methylation is prevented by the maintenance of a euchromatic mark over CpG island chromatin. A better understanding of the mechanisms underlying the genesis and consequences of aberrant DNA methylation during carcinogenesis will provide for the future development of novel treatment strategies aimed at preventing or reversing the silencing process.
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2009 — 2013 |
Vertino, Paula M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Defining Genomic Signatures For Aberrant Dna Methylation in Human Cancers
DESCRIPTION (provided by applicant): Epigenetic silencing involving alterations in DNA methylation and chromatin structure at promoter region CpG islands is a common mechanism of tumor suppressor gene inactivation in human cancers. However, the mechanisms underlying this event remain poorly understood. An unresolved question is why are some genes targets of aberrant methylation in human cancers while others are never affected? In preliminary work, we have shown that even in the context of an increased cellular capacity for de novo methylation, CpG islands differ in their potential for aberrant methylation. By applying DNA pattern recognition and machine learning techniques, we have developed an algorithm based on several short sequence patterns that is capable of accurately discriminating methylation-prone and methylation-resistant CpG islands. These studies indicate that the epigenetic status of a CpG island can be predicted based on DNA sequence features, and lead us to propose that one factor contributing to the non-random patterns of CpG island methylation observed in human tumors is an underlying susceptibility conferred by local sequence context. The goal of this proposal is to define the genomic signature associated with aberrant methylation. The long term objectives are (i) to identify and to functionally characterize local sequence attributes that contribute to the propensity towards, or protection from, aberrant methylation, and (ii) to develop and to test novel tumor specific classifiers capable of predicting genomic loci at risk of aberrant methylation. Specifically, we will determine whether sequence features identified in silico act in cis to promote or to prevent de novo methylation in vivo using an episomal transgene approach. In preliminary work, we have identified a relationship between methylation-prone CpG islands and genomic regions bound by the polycomb repressor complex. As a second component of the project, we will determine the role of PRC2 in methylation susceptibility. As a third component of this project we will refine our computational models by 1) determining whether CpG islands predicted to be methylation-prone are in fact targets of aberrant methylation in human cancers, 2) using this information to re-train the prediction model, and 3) developing and testing a novel lung cancer specific classifier based on large-scale CpG island methylation data from primary lung tumors. We anticipate that the information gained from these studies will allow for a better understanding of the mechanisms underlying the epigenetic silencing of tumor suppressor genes that accompanies carcinogenesis. Moreover, the ability to predict the methylation status of CpG islands genome-wide will provide an important resource for the identification of novel gene targets for further study as potential cancer biomarkers.
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2012 — 2020 |
Vertino, Paula M. |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Cancer Genetics and Epigenetics
PROJECT SUMMARY/ABSTRACT The Cancer Genetics and Epigenetics (CGE) Program of Winship Cancer Institute of Emory University is a laboratory-based basic science program that seeks to better understand how altered genetic and epigenetic components of the genome contribute to the initiation and progression of human cancers. Under the leadership of Paula Vertino, PhD (leader) and Jin-Tang Dong, PhD (co-leader) the CGE Program includes 27 core members drawn from 14 departments and three schools across Emory University, including the School of Medicine, Emory College, and Rollins School of Public Health. The goals of the CGE program are to better understand the mechanisms that govern the maintenance of genome stability and proper gene regulatory networks, how these become corrupted in cancer cells, and how their disruption contributes to the initiation and progression of cancer. The CGE Program seeks to promote the expanded application of genomic technologies in the molecular classification of cancer phenotypes and outcomes. The scientific focus of the program is organized around three inter-related and complimentary themes: (1) DNA Damage, Repair, and Cellular Responses to Stress, (2) Epigenetics and Gene Regulation, and (3) Cancer Genetics and Genomics. Over the last competitive cycle CGE Program members have published 256 cancer-relevant scientific articles. Of these, 55 (21%) were intra- and 105 (41%) were inter-programmatic collaborations, and 123 (48%) represented a collaboration with another cancer center or other academic organization. As of March 31, 2016, CGE held $9.1 million in annual total cancer-relevant research funding, of which approximately $3 million (33%) was awarded from the NCI. Strong scientific synergism has led to important discoveries. Key insights into the mechanism of DNA double strand break repair, how replication stress is resolved, and radiation mutagenesis are leading to important predictors of chemotherapy and radiation response. Landmark investigations into the structure and function of the TET dioxygenase enzymes have revealed oxidized methylcytosine residues to be more than a transient intermediate in the turnover of 5mC, but a distinct component of the epigenetic `code' governing gene expression programs. Significant strides have been taken towards the successful translation of the program's genetics/genomics efforts, including new insight into the contribution of key `driver' gene mutations and the unique cellular vulnerabilities that such alterations unmask, an RNA-based biomarker panel for the early detection of aggressive prostate cancer, a combined RNA-DNA test for risk stratification in oropharyngeal carcinomas, and the implementation of a clinical genomics workflow to guide decision making in several cancer types. Overall, the CGE Program promotes center-wide goals for improvements in cancer outcomes across the state of Georgia by identifying of key points of cancer cell vulnerability that can be exploited towards new therapeutic opportunities and the development of genomic and epigenomic signatures as predictors of clinical outcomes and population risk.
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