Various hypotheses have been put forward to explain the aging process at both the cellular and organismal level. Among the most popular ones are accumulation of nuclear and mitochondrial DNA damage and mutations, damage to macromolecules induced by oxidative stress and other intrinsic chemical reactions, telomere erosion and dysfunction, activation of oncogenes, and a deterioration of stem cell renewal in proliferating tissues. Most likely, an overlap of all of these phenomena will contribute to cellular and organismal aging. However, here we propose a new paradigm: that alterations of the epigenome contribute substantially to the aging process. In this application, we propose that epigenetic changes are a hallmark of aging. We will analyze several epigenetic marks including DNA CpG methylation and chromatin modifications in cells that undergo aging in vitro and in vivo. In addition, we will analyze these marks in Cockayne syndrome cells, a premature aging syndrome. This epigenome mapping project will make use of the methylated CpG island recovery assay (MIRA) technique for DNA methylation analysis and chromatin immunoprecipitation for analysis of histone modifications. Genome-wide analysis will be accomplished by microarray and high throughput DNA sequence analysis. This grant proposes an in-depth analysis of the epigenome, at the level of histone modifications, DNA methylation and gene expression during the time course of aging and in premature aging syndromes. A homogenous cell type derived from identical body sites and obtained serially from the same individuals will enable us to make meaningful comparisons. The data will allow an estimation of the extent and specificity of epigenetic changes that occur during the aging process, and hence we will be in a position to better assess the exact contribution of epigenetics to aging.

Public Health Relevance

In this application, we propose that epigenetic changes are a hallmark of the aging process. We will analyze several epigenetic marks including DNA CpG methylation and chromatin modifications in cells that undergo aging in vitro and in vivo. In addition, we will analyze these marks in Cockayne syndrome cells, a premature aging syndrome. This epigenome mapping project will make use of the methylated CpG island recovery assay (MIRA) technique for DNA methylation analysis and chromatin immunoprecipitation for analysis of histone modifications. Genome-wide analysis will be accomplished by microarray and high throughput DNA sequence analysis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG036041-04
Application #
8306204
Study Section
Special Emphasis Panel (ZRG1-GGG-M (53))
Program Officer
Petanceska, Suzana
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$394,909
Indirect Cost
$157,012
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Iqbal, Khursheed; Jin, Seung-Gi; Pfeifer, Gerd P et al. (2011) Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A 108:3642-7
Hahn, Maria A; Wu, Xiwei; Li, Arthur X et al. (2011) Relationship between gene body DNA methylation and intragenic H3K9me3 and H3K36me3 chromatin marks. PLoS One 6:e18844
Jin, Seung-Gi; Wu, Xiwei; Li, Arthur X et al. (2011) Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39:5015-24
Lee, Dong-Hoon; Tran, Diana A; Singh, Purnima et al. (2011) MIRA-SNuPE, a quantitative, multiplex method for measuring allele-specific DNA methylation. Epigenetics 6:212-23
Jin, Seung-Gi; Jiang, Yong; Qiu, Runxiang et al. (2011) 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res 71:7360-5
Rauch, Tibor A; Pfeifer, Gerd P (2010) DNA methylation profiling using the methylated-CpG island recovery assay (MIRA). Methods 52:213-7