Germ cells maintain themselves in a pristine condition that allows for indefinite proliferation as they are passed from one generation to the next. In contrast, somatic cells, including somatic stem cells, are only needed for a single generation and may be deficient for mechanisms that ensure an unlimited proliferative capacity. This dichotomy between germ and soma cells may be the ultimate cause of human proliferative aging and may contribute to some age-related diseases such as tumorigenesis. The long-term goal of this project is to study the mechanisms by which germ cells maintain an unlimited proliferative capacity. We discovered that the C. elegans Piwi homolog prg-1 promotes germ cell immortality via small RNA-mediated silencing of the epigenome and that the transgenerational fertility defect of Piwi/piRNA mutants can be suppressed by activation of a major somatic longevity pathway. We propose 1) to study how the insulin/IGF-1 signaling pathway suppresses the transgenerational fertility defect of Piwi mutants, 2) to study the sterilit phenotype of Piwi mutants, which may represent a state of suspended animation, and 3) to more thoroughly explore how the transgenerational sterility phenotype of Piwi mutants can be suppressed. The proposed experiments should provide insight into 1) a form of heritable epigenetic stress that can be transmitted by germ cells and 2) the organismal response to high levels of this stress. We could uncover fundamental principles relevant to transgenerational regulation of aging.

Public Health Relevance

Germ cells maintain themselves in a pristine condition that allows for indefinite proliferation as they are passed from one generation to the next. In contrast somatic cells, including somatic stem cells, are only needed for a single generation and may be deficient for mechanisms that ensure an unlimited proliferative capacity. This dichotomy between germ and soma cells may be the ultimate cause of human proliferative aging and may contribute to some age-related diseases such as tumorigenesis. The long-term goal of this project is to study the mechanisms by which germ cells maintain an unlimited proliferative capacity. We discovered that the C. elegans Piwi homolog prg-1 promotes germ cell immortality via small RNA-mediated silencing of the epigenome and that the transgenerational fertility defect of Piwi/piRNA mutants can be suppressed by activation of a major somatic longevity pathway. We propose 1) to study how the insulin/IGF-1 signaling pathway suppresses the transgenerational fertility defect of Piwi mutants, 2) to study the sterility phenotype of Piwi mutants, which may represent a state of suspended animation, and 3) to more thoroughly explore how the transgenerational sterility phenotype of Piwi mutants can be suppressed. The proposed experiments should provide insight into 1) a form of heritable epigenetic stress that can be transmitted by germ cells and 2) the organismal response to high levels of this stress. We could uncover fundamental principles relevant to transgenerational regulation of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM083048-08
Application #
9389508
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Salazar, Desiree Lynn
Project Start
2007-09-17
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Heestand, Bree; Simon, Matt; Frenk, Stephen et al. (2018) Transgenerational Sterility of Piwi Mutants Represents a Dynamic Form of Adult Reproductive Diapause. Cell Rep 23:156-171
Frenk, Stephen; Houseley, Jonathan (2018) Gene expression hallmarks of cellular ageing. Biogerontology 19:547-566
Leopold, Luciana E; Heestand, Bree N; Seong, Soobin et al. (2015) Lack of pairing during meiosis triggers multigenerational transgene silencing in Caenorhabditis elegans. Proc Natl Acad Sci U S A 112:E2667-76
Alvares, Stacy M; Mayberry, Gaea A; Joyner, Ebony Y et al. (2014) H3K4 demethylase activities repress proliferative and postmitotic aging. Aging Cell 13:245-53
Sakaguchi, Aisa; Sarkies, Peter; Simon, Matt et al. (2014) Caenorhabditis elegans RSD-2 and RSD-6 promote germ cell immortality by maintaining small interfering RNA populations. Proc Natl Acad Sci U S A 111:E4323-31
Simon, Matt; Sarkies, Peter; Ikegami, Kohta et al. (2014) Reduced insulin/IGF-1 signaling restores germ cell immortality to Caenorhabditis elegans Piwi mutants. Cell Rep 7:762-73
Ashe, Alyson; Sapetschnig, Alexandra; Weick, Eva-Maria et al. (2012) piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans. Cell 150:88-99