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.
Proceedings of the National Academy of Sciences of the United States of America. 2016 Aug 31 [Epub ahead of print]
Delphine Carouge, Valerie Blanc, Sue E Knoblaugh, Robert J Hunter, Nicholas O Davidson, Joseph H Nadeau
Pacific Northwest Research Institute, Seattle, WA 98122;, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110;, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210;, Preclinical Research and Transgenic Services, University of Washington, Seattle, WA 98195., Pacific Northwest Research Institute, Seattle, WA 98122; .