The goal of this proposal is to explore the transgenerational epigenetic inheritance of longevity. A fundamental question is whether epigenetic changes that affect lifespan in the parental generation can still impact the lifespan of the subsequent generations even when the factors that led to these changes are no longer present. While some evidence of transgenerational epigenetic inheritance for simple traits exist, very little is known about the transgenerational inheritance of acquired complex traits. Understanding the epigenetic memory of longevity between generations has the potential to revolutionize the current paradigm on the inheritance of complex diseases and will also have a broad impact on our understanding of epigenome reprogramming. We recently made the surprising discovery that mutations in specific regulators of trimethylated lysine 4 on histone H3 (H3K4me3) in parents lead to lifespan extension in descendants for up to three generations, even after the initial mutation is no longer present. This unexpected discovery has led our lab in a new direction. The questions we ask are: what are the mechanisms underlying transgenerational epigenetic inheritance of longevity? Is epigenetic memory of lifespan generalizable to vertebrates? Could environmental factors that affect aging, such as dietary intake, impact subsequent generations even when the environment is back to normal? Could this unconventional mode of inheritance have the evolutionary advantage of 'informing'future generations about the ancestors'environment? We will develop an innovative and exciting framework to address transgenerational inheritance of longevity experimentally. A major goal will be to systematically identify the molecules that are inherited in a transgenerational manner and that mediate this epigenetic memory by combining unbiased genomics, proteomics and metabolomics technologies and single-cell approaches. Another challenge will be to examine the importance of epigenet

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1AG044848-01
Application #
8351884
Study Section
Special Emphasis Panel (ZGM1-NDPA-A (01))
Program Officer
Guo, Max
Project Start
2012-09-30
Project End
2017-07-31
Budget Start
2012-09-30
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$785,000
Indirect Cost
$285,000
Name
Stanford University
Department
Genetics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Hu, Chi-Kuo; Brunet, Anne (2018) The African turquoise killifish: A research organism to study vertebrate aging and diapause. Aging Cell 17:e12757
Dulken, Ben W; Leeman, Dena S; Boutet, Stéphane C et al. (2017) Single-Cell Transcriptomic Analysis Defines Heterogeneity and Transcriptional Dynamics in the Adult Neural Stem Cell Lineage. Cell Rep 18:777-790
Russell, James J; Theriot, Julie A; Sood, Pranidhi et al. (2017) Non-model model organisms. BMC Biol 15:55
Han, Shuo; Schroeder, Elizabeth A; Silva-García, Carlos G et al. (2017) Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan. Nature 544:185-190
Smith, C T; Dang, L C; Buckholtz, J W et al. (2017) The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum. Transl Psychiatry 7:e1091
Daugherty, Aaron C; Yeo, Robin W; Buenrostro, Jason D et al. (2017) Chromatin accessibility dynamics reveal novel functional enhancers in C. elegans. Genome Res 27:2096-2107
Booth, Lauren N; Brunet, Anne (2016) The Aging Epigenome. Mol Cell 62:728-44
Smith, Christopher T; Dang, Linh C; Cowan, Ronald L et al. (2016) Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine. Neuropharmacology 108:394-402
Harel, Itamar; Benayoun, Bérénice A; Machado, Ben et al. (2015) A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Cell 160:1013-1026
Benayoun, Bérénice A; Pollina, Elizabeth A; Brunet, Anne (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16:593-610

Showing the most recent 10 out of 15 publications