Inhibitor of Normal Growth (ING)

ING 2（inhibitor of growth family，member 2）是公认的肿瘤抑制因子ING家族的成员。ING 2与组蛋白H3的三甲基化赖氨酸4（H3 K4 me 3）结合以调节染色质修饰和基因表达。ING 2还在功能上与肿瘤抑制蛋白p53相互作用，以在体外调节细胞衰老、凋亡和DNA损伤反应，因此预期其调节癌发生和衰老。在这里，我们通过有针对性的生殖系破坏研究Ing 2的发育和生理功能。与其在小鼠和人睾丸中的丰富表达一致，缺乏Ing 2的雄性小鼠表现出精子发生异常并且不育。Ing 2-/-小鼠的成熟精子数量和精子活力显著降低（分别为野生型的约2%，P <0.0001和约野生型的10%，P <0.0001）。其睾丸表现为曲细精管变性，粗线期前减数分裂停滞，减数分裂重组不完全，p53诱导，细胞凋亡增强。这种表型仅部分废除伴随的损失p53在生殖系。在Ing 2-/-睾丸中被逮捕的精母细胞的特点是缺乏特定的HDAC 1积累和去调节染色质乙酰化。Ing 2在生殖细胞成熟中的作用也可能延伸到人ING 2。使用公开可用的基因表达数据集，在畸形精子症精子（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）中发现了ING 2的低表达。这项研究建立了ING 2作为一种新的调节精子发生的功能，通过p53和染色质介导的机制，并表明HDAC 1/ING 2/H3 K4 me 3调节，阶段特异性协调染色质修饰是必不可少的正常精子发生，并提供了一个动物模型，以研究男性特发性和医源性不育。此外，Ing 2-/-小鼠软组织肉瘤发病率增加证明了Ing 2的真正肿瘤抑制作用。

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.