Poster Sessions

DEV-14

Motonobu Saito

K. Kumamoto, I. Horikawa, A.I. Robles, A. Goto, T. Yamashita, S. Takenoshita, J. Yokota, S.P. Hussain, G.E. Trivers, C.C. Harris

ING2 is a Novel Regulator of Mammalian Spermatogenesis That Functions through Chromatin Modifications

Inhibitor of growth 2 (ING2) binds to trimethylated lysine 4 of histone H3 (H3K4) via its plant homeodomain (PHD) finger and recruits mSin3A-HDAC1 histone deacetylase complex. To examine in vivo physiological roles of ING2 for the first time, we have generated Ing2-deficient mice. While mice deficient for Ing2 were born and grew without apparent abnormalities, male, but not female, were infertile, consistent with the highest expression of Ing2 in testes in wild-type mice. Histological and DNA content analyses in Ing2-/- testes revealed a spermatogenesis arrest at meiotic phase and enhanced apoptosis associated with increased p53, resulting in a decline in mature spermatozoa, which became more severe in older age. HDAC1 accumulation and core histone deacetylation at pachytene stage were impaired in Ing2-/- testes, suggesting that the recruitment of HDAC1 by Ing2 plays a critical role in spermatogenesis. This study establishes Ing2 as a novel mammalian regulator of spermatocyte differentiation, which coordinates spermatogenesis stage-specific histone modifications. Given that testes are also the organs with most abundant ING2 expression in humans, this study has implications in understanding human male infertility.