The adult germ line has many disparate functions, including proliferation, meiotic synapsis and recombination, maternal and paternal mRNA and protein synthesis, and gametogenesis. It also has multiple obligations, including preventing mobile genetic elements (transposons) from inflicting heritable genetic damage, preventing differentiation of the germ cells into somatic cells, and establishing heritable states of transcriptional activity. All of these obligations are met, to some extent, by repressive mechanisms that act to silence or prevent inappropriate activities that are counter to these obligations. Germ cell repression utilizes a combination of post-transcriptional repression (e.g., RNAi-based) and transcriptional (e.g., chromatin based) mechanisms to achieve its goals. A major target of these mechanisms is the X chromosome, which is transcriptionally repressed during meiosis in both sexes in C. elegans, but is fully inactivated during male meiosis in both worms and mammals. Sex chromosome inactivation is mediated by a highly conserved process that targets unsynapsed chromatin during meiosis, and is likely an ancient genome defense mechanism. We understand some of the components of the mechanism, and plan to further dissect the mechanism and its regulation using C. elegans as a model system. In both mammals and worms, the male X is """"""""imprinted"""""""" for preferentially inactivation in embryos, and this is likely a consequence of its meiotic silencing. Imprinted X inactivation is a dramatic example of genetic imprinting, and little is understood about imprint establishment. We will also use the genetic, molecular, biochemical, and cytological tools available in C. elegans to dissect the mechanism of male X imprinting. We have used the extensive tools available for this organism to build it into an excellent model organism for studying germ line repression, or silencing, and are now poised to dissect the role of chromatin in germ cell silencing, imprint establishment and genome defense mechanisms in this genetic model system. Epigenetic mechanisms operating in the germ line are essential for the establishment of imprinting and the prevention of heritable genetic mutations, both of which are crucial for normal human health and normal human development. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063102-07
Application #
7457783
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
2002-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
7
Fiscal Year
2008
Total Cost
$306,000
Indirect Cost
Name
Emory University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Arico, Jackelyn K; Katz, David J; van der Vlag, Johan et al. (2011) Epigenetic patterns maintained in early Caenorhabditis elegans embryos can be established by gene activity in the parental germ cells. PLoS Genet 7:e1001391
Li, Tengguo; Kelly, William G (2011) A role for Set1/MLL-related components in epigenetic regulation of the Caenorhabditis elegans germ line. PLoS Genet 7:e1001349
She, Xingyu; Xu, Xia; Fedotov, Alexander et al. (2009) Regulation of heterochromatin assembly on unpaired chromosomes during Caenorhabditis elegans meiosis by components of a small RNA-mediated pathway. PLoS Genet 5:e1000624
Whittle, Christina M; McClinic, Karissa N; Ercan, Sevinc et al. (2008) The genomic distribution and function of histone variant HTZ-1 during C. elegans embryogenesis. PLoS Genet 4:e1000187
Kelly, William G; Aramayo, Rodolfo (2007) Meiotic silencing and the epigenetics of sex. Chromosome Res 15:633-51
Checchi, Paula M; Kelly, William G (2006) emb-4 is a conserved gene required for efficient germline-specific chromatin remodeling during Caenorhabditis elegans embryogenesis. Genetics 174:1895-906
Walstrom, Katherine M; Schmidt, Deborah; Bean, Christopher J et al. (2005) RNA helicase A is important for germline transcriptional control, proliferation, and meiosis in C. elegans. Mech Dev 122:707-20
Schaner, Christine E; Deshpande, Girish; Schedl, Paul D et al. (2003) A conserved chromatin architecture marks and maintains the restricted germ cell lineage in worms and flies. Dev Cell 5:747-57