More than 1,000 published GWAS have collectively reported significant associations of ~4,000 SNPs for more than 200 traits/diseases. The challenge is to move SNP associations to biological insights and then to translate these insights, achieving better clinical outcomes. This ambitious goal requires an inclusive and effective strategy to solve the molecular basis by which these variants confer disease susceptibility. To date, the vast majority of the associations noted in GWAS for disease phenotypes have been with variants located within gene deserts, the 99% of the genome that does not encode known proteins and where our understanding of functional consequences and causality is at best rudimentary. Recent findings indicate that altering DNA sequence in evolutionarily conserved non-coding regions can be as deleterious as altering coding regions. Therefore, it is not surprising that disease-causing variants will reside in the gene desert regions. The greatest challenge in the """"""""post-GWAS"""""""" era is to understand the regulatory principles of risk variants in gene desert regions and the mechanisms underlying the risk conferred by these loci. The goal of this proposal is to accelerate post-GWAS functional characterization, uncovering initial global principles for the functional characterization of disease risk loci by focusing on altered function in transcription based on the actions of enhancer RNAs. Employing the 9p21 region as a model, we will establish how disease-associated common sequence variants alter the functions of regulatory regions and address the molecular mechanisms by which these effects are exerted. These studies will integrate disease susceptibility-associated sequence variations into the emerging three-dimensional network of long-distance genomic region interactions, establish local and global alterations in gene transcription, and explore the key role of enhancer-RNAs harboring sequence variations at GWAS loci. The primary significance will be the discovery of a novel functional consequences and an """"""""epigenomic"""""""" molecular mechanism underlying GWAS loci in disease, with the opportunity for exploiting these new mechanistic and therapeutic insights for preventative approaches to the chronic diseases associated with aging.

Public Health Relevance

The rapid development and deployment of high-throughput, genome-wide technologies coupled to advances in our understanding of transcription, the regulatory strategies of epigenetics and nuclear architecture, and the roles of non-coding RNA (ncRNA) in human biology and disease has licensed new, challenging approaches to functionally link GWAS disease risk loci to various molecular pathways. In this application, we propose to apply these approaches to test a novel paradigm for global transcriptional program changes underlying disease susceptibility detected by GWAS in humans, employing the 9p21 region as a model. Three-dimensional enhancer:promoter interactions, global patterns of altered transcription, gene relocations between functionally distinct subnuclear architectural structures and roles of eRNAs will be investigated. Based on the preliminary data and given all the permissive technologies currently operational in our laboratories, we believe that this project, central to exploiting the insights emanating from contemporary genetic studies of disease susceptibility, will provide critical insights into new strategies for disease prevention and therapeutic approaches, as well as making central contributions to the problem of enhancer-dependent gene transcription programs. The goal is to provide novel targets to prevent or inhibit disease-associated events and perhaps senescence in human cells. The 9p21, model will therefore provide an experimental blueprint for study of any GWAS locus. DESCRIPTION (provided by applicant): More than 1,000 published GWAS have collectively reported significant associations of ~4,000 SNPs for more than 200 traits/diseases. The challenge is to move SNP associations to biological insights and then to translate these insights, achieving better clinical outcomes. This ambitious goal requires an inclusive and effective strategy to solve the molecular basis by which these variants confer disease susceptibility. To date, the vast majority of the associations noted in GWAS for disease phenotypes have been with variants located within gene deserts, the 99% of the genome that does not encode known proteins and where our understanding of functional consequences and causality is at best rudimentary. Recent findings indicate that altering DNA sequence in evolutionarily conserved non-coding regions can be as deleterious as altering coding regions. Therefore, it is not surprising that disease-causing variants will reside in the gene desert regions. The greatest challenge in the post-GWAS era is to understand the regulatory principles of risk variants in gene desert regions and the mechanisms underlying the risk conferred by these loci. The goal of this proposal is to accelerate post-GWAS functional characterization, uncovering initial global principles for the functional characterization of disease risk loci by focusing on altered function in transcription based on the actions of enhancer RNAs. Employing the 9p21 region as a model, we will establish how disease-associated common sequence variants alter the functions of regulatory regions and address the molecular mechanisms by which these effects are exerted. These studies will integrate disease susceptibility-associated sequence variations into the emerging three-dimensional network of long-distance genomic region interactions, establish local and global alterations in gene transcription, and explore the key role of enhancer-RNAs harboring sequence variations at GWAS loci. The primary significance will be the discovery of a novel functional consequences and an epigenomic molecular mechanism underlying GWAS loci in disease, with the opportunity for exploiting these new mechanistic and therapeutic insights for preventative approaches to the chronic diseases associated with aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM104459-01
Application #
8431585
Study Section
Special Emphasis Panel (ZGM1-GDB-7 (CP))
Program Officer
Krasnewich, Donna M
Project Start
2013-04-05
Project End
2017-01-31
Budget Start
2013-04-05
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$628,550
Indirect Cost
$144,050
Name
Albert Einstein College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Milholland, Brandon; Suh, Yousin; Vijg, Jan (2017) Mutation and catastrophe in the aging genome. Exp Gerontol 94:34-40
Lau, Cia-Hin; Suh, Yousin (2017) Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease. Gerontology 63:103-117
Zhu, Yizhou; Tazearslan, Cagdas; Suh, Yousin (2017) Challenges and progress in interpretation of non-coding genetic variants associated with human disease. Exp Biol Med (Maywood) 242:1325-1334
Jung, Hwa Jin; Lee, Kwang-Pyo; Milholland, Brandon et al. (2017) Comprehensive miRNA Profiling of Skeletal Muscle and Serum in Induced and Normal Mouse Muscle Atrophy During Aging. J Gerontol A Biol Sci Med Sci 72:1483-1491
Ryu, Seungjin; Atzmon, Gil; Barzilai, Nir et al. (2016) Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. Mech Ageing Dev 155:7-9
Olivieri, Fabiola; Capri, Miriam; Bonafè, Massimiliano et al. (2016) Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging. Mech Ageing Dev :
Johnson, Simon C; Dong, Xiao; Vijg, Jan et al. (2015) Genetic evidence for common pathways in human age-related diseases. Aging Cell 14:809-17
Puc, Janusz; Kozbial, Piotr; Li, Wenbo et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367-80
Park, Caroline; Suh, Yousin; Cuervo, Ana Maria (2015) Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nat Commun 6:6823
Li, Wenbo; Hu, Yiren; Oh, Soohwan et al. (2015) Condensin I and II Complexes License Full Estrogen Receptor ?-Dependent Enhancer Activation. Mol Cell 59:188-202

Showing the most recent 10 out of 17 publications