Inhibitor of Normal Growth (ING)

ING2(生长抑制因子家族，成员2)是ING家族中可能的肿瘤抑制因子。ING2与组蛋白H3(H3K4me3)的三甲基化赖氨酸4(H3K4me3)结合，调节染色质修饰和基因表达。ING2还在功能上与肿瘤抑制蛋白P53相互作用，在体外调节细胞衰老、细胞凋亡和DNA损伤反应，因此有望调节肿瘤的发生和衰老。在这里，我们通过有针对性的生殖系破坏来研究Ing2的发育和生理功能。与其在小鼠和人类睾丸中的大量表达一致，缺乏Ing2的雄性小鼠表现出生精异常和不育。Ing2-/-小鼠成熟精子数和精子活动率显著降低(野生型的约2%，P<0.0001；野生型的约10%，P<0.0001)。他们的睾丸表现为曲细精管变性，粗线期之前减数分裂停止，减数分裂重组不完全，P53被诱导，细胞凋亡增强。这一表型仅因生殖系中伴随的P53基因缺失而部分丧失。Ing2-/-睾丸中受阻的精母细胞的特征是缺乏特异性的HDAC1积聚和去调节的染色质乙酰化。Ing2在生殖细胞成熟中的作用也可能延伸到人类ING2。使用公开的基因表达数据集，ING2在畸形精子(减少3倍以上)和精子发生缺陷患者的睾丸(仅支持细胞综合征减少7倍以上)中低表达。本研究建立了ING2作为一种新的精子发生调节因子，通过P53和染色质介导的机制，并提示HDAC1/ING2/H3K4me3调节的染色质修饰的阶段特异性协调对于正常的精子发生是必不可少的，并为研究男性特发性和医源性不育提供了一个动物模型。此外，ING2-/-小鼠软组织肉瘤发病率的增加也证明了ING2具有真正的肿瘤抑制作用。

ING2 (inhibitor of growth family, member 2) is a member of the ING family of putative tumor suppressors. ING2 binds to tri-methylated lysine 4 of histone H3 (H3K4me3) to regulate chromatin modification and gene expression. ING2 also functionally interacts with the tumor suppressor protein p53 to regulate cellular senescence, apoptosis and DNA damage response in vitro, and is thus expected to modulate carcinogenesis and aging. Here we investigate the developmental and physiological functions of Ing2 through targeted germline disruption. Consistent with its abundant expression in mouse and human testes, male mice deficient for Ing2 showed abnormal spermatogenesis and were infertile. Numbers of mature sperm and sperm motility were significantly reduced in Ing2-/- mice (approximately 2% of wild type, P less than 0.0001 and approximately 10% of wild type, P less than 0.0001, respectively). Their testes showed degeneration of seminiferous tubules, meiotic arrest before pachytene stage with incomplete meiotic recombination, induction of p53, and enhanced apoptosis. This phenotype was only partially abrogated by concomitant loss of p53 in the germline. The arrested spermatocytes in Ing2 -/- testes were characterized by lack of specific HDAC1 accumulation and deregulated chromatin acetylation. The role of Ing2 in germ cell maturation may extend to human ING2 as well. Using publicly available gene expression datasets, low expression of ING2 was found in teratozoospermic sperm (greater than 3-fold reduction) and in testes from patients with defective spermatogenesis (greater than 7-fold reduction in Sertoli-cell only Syndrome). This study establishes ING2 as a novel regulator of spermatogenesis functioning through both p53- and chromatin-mediated mechanisms and suggests that an HDAC1/ING2/H3K4me3-regulated, stage-specific coordination of chromatin modifications is essential to normal spermatogenesis, and provides an animal model to study idiopathic and iatrogenic infertility in men. In addition, a bona fide tumor suppressive role of Ing2 is demonstrated by increased incidence of soft-tissue sarcomas in Ing2-/- mice.