title: Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias.
abstract: Testicular tumors, the most common cancer in young men, arise from abnormalities in germ cells during fetal development. Unconventional inheritance for testicular germ cell tumor (TGCT) risk both in humans and mice implicates epigenetic mechanisms. Apolipoprotein B mRNA-editing enzyme complex 1 (APOBEC1) cytidine deaminase and Deadend-1, which are involved in C-to-U RNA editing and microRNA-dependent mRNA silencing, respectively, are potent epigenetic modifiers of TGCT susceptibility in the genetically predisposed 129/Sv inbred mouse strain. Here, we show that partial loss of either APOBEC1 complementation factor (A1CF), the RNA-binding cofactor of APOBEC1 in RNA editing, or Argonaute 2 (AGO2), a key factor in the biogenesis of certain noncoding RNAs, modulates risk for TGCTs and testicular abnormalities in both parent-of-origin and conventional genetic manners. In addition, non-Mendelian inheritance was found among progeny of A1cf and Ago2 mutant intercrosses but not in backcrosses and without fetal loss. Together these findings suggest nonrandom union of gametes rather than meiotic drive or preferential lethality. Finally, this survey also suggested that A1CF contributes to long-term reproductive performance. These results directly implicate the RNA-binding proteins A1CF and AGO2 in the epigenetic control of germ-cell fate, urogenital development, and gamete functions.
authors: Pacific Northwest Research Institute, Seattle, WA 98122;
authors: Delphine
authors: D
authors: Carouge
authors: Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110;
authors: Valerie
authors: V
authors: Blanc
authors: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210;
authors: Sue E
authors: SE
authors: Knoblaugh
authors: Preclinical Research and Transgenic Services, University of Washington, Seattle, WA 98195.
authors: Robert J
authors: RJ
authors: Hunter
authors: Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110;
authors: Nicholas O
authors: NO
authors: Davidson
authors: Pacific Northwest Research Institute, Seattle, WA 98122; jnadeau@pnri.org.
authors: Joseph H
authors: JH
authors: Nadeau
mesh_terms: D000071479:APOBEC-1 Deaminase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005854:Germ Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000473:pathology; D017393:RNA Editing / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C411647:A1CF protein, human; C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D000071479:APOBEC-1 Deaminase
keywords: A1CF; AGO2; epigenetic inheritance; parent-of-origin effects; testicular cancer