Abstract 4890: ING2, a p53- and chromatin-interacting protein, is essential to mammalian spermatogenesis: Implications in male infertility in humans

Abstract

Abstract ING2 (inhibitor of growth family, member 2) plays pivotal roles in the regulation of cellular senescence, apoptosis, DNA damage repair, gene transcription and chromatin modification. Our previous in vitro studies on cellular senescence suggested that ING2 functionally interplays with the p53 tumor suppressor protein in two different manners: endogenous ING2 inhibits senescence and the transcriptional repression of ING2 by p53 abrogates this inhibition; and overexpressed ING2 enhances p53 acetylation and stability to induce senescence. ING2, as a subunit of the mSin3A-HDAC1 (histone deacetylase 1) complex, specifically binds to tri-methylated lysine 4 of histone H3 (H3K4me3) via its plant homeodomain (PHD) finger and regulates gene expression through chromatin modifications in response to DNA damage. This study investigates the in vivo developmental and physiological functions of ING2. Abundant expression of ING2 in mouse and human testes and its decreased expression associated with male infertility and defective spermatogenesis in humans suggested an essential role of ING2 in spermatogenesis, which is a process tightly regulated by chromatin modifications. Consistently, male mice deficient for Ing2 were infertile. Their testes had degeneration of seminiferous tubules, which became more severe with age, and showed enhanced p53-dependent and -independent apoptosis. Spermatogenesis arrest at meiotic phase in Ing2−/− testes was due to impaired HDAC1 accumulation and deregulated chromatin acetylation. This study establishes ING2 as a novel mammalian regulator of spermatogenesis, suggests that an HDAC1/ING2/H3K4me3-regulated, stage-specific coordination of chromatin modifications is essential to normal spermatogenesis, and provides a model system to study idiopathic and iatrogenic infertility in men, including those who had cancer chemotherapy and radiotherapy. Spontaneous tumor incidence and spectrum were similar in wild-type and Ing2-deficient mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4890.