Al Shueili Buthaina, Dantas Arthur, Mahe Etienne, Chu Tak Ho, Yang Yang, Labit Elodie, Kutluberk Eren, Lasaleta Nicolas, Masson Anand, Omairi Hiba, Ito Kenichi, Krawetz Roman J, Midha Rajiv, Cairncross Gregory, Riabowol Karl
Robson DNA Sciences Centre, Calgary, Canada.
Arnie Charbonneau Cancer Institute, Calgary, Canada.
PLoS One. 2025 Jan 9;20(1):e0313255. doi: 10.1371/journal.pone.0313255. eCollection 2025.
INhibitor of Growth (ING1-5) proteins are epigenetic readers that target histone acetyltransferase (HAT) or histone deacetylase (HDAC) complexes to the H3K4Me3 mark of active transcription. ING5 targets Moz/Morf and HBO1 HAT complexes that alter acetylation of H3 and H4 core histones, affecting gene expression. Previous experiments in vitro indicated that ING5 functions to maintain stem cell character in normal and in cancer stem cells. Here we find that CRISPR/Cas9 ING5 knockout (KO) mice are sub-fertile but show no decrease in lifespan or ability to heal wounds despite indications of depleted stem cell pools in several tissues. ING5 KO mouse embryo fibroblasts accumulate in G2 of the cell cycle, have high levels of abnormal nuclei and show high basal levels of the γH2AX indicator of DNA damage. KO animals also develop severe dermatitis at a 5-fold higher rate that wild-type littermates. Consistent with ING5 serving a tumor suppressive role, ING5 KO mice developed germinal centre diffuse large B-cell lymphomas at a rate 6-fold higher than control mice at 18 months of age. These data suggest that ING5 functions in vivo to maintain stem cell character in multiple organs, that reduction of stem cell populations is not limiting for murine lifespan and that like a subset of other ING family members, ING5 functions as a tumor suppressor in hematopoietic cells in vivo.
生长抑制因子（ING1-5）蛋白是表观遗传阅读器，可将组蛋白乙酰转移酶（HAT）或组蛋白去乙酰化酶（HDAC）复合物靶向至活跃转录的H3K4Me3标记。ING5靶向Moz/Morf和HBO1 HAT复合物，这些复合物会改变H3和H4核心组蛋白的乙酰化，从而影响基因表达。先前的体外实验表明，ING5在维持正常干细胞和癌症干细胞的特性方面发挥作用。在此，我们发现CRISPR/Cas9介导的ING5基因敲除（KO）小鼠生育力低下，但尽管有迹象表明多个组织中的干细胞池减少，但它们的寿命或伤口愈合能力并未降低。ING5基因敲除的小鼠胚胎成纤维细胞在细胞周期的G2期积累，有大量异常细胞核，并且显示出高水平的DNA损伤γH2AX指标。基因敲除动物发生严重皮炎的几率也比野生型同窝小鼠高5倍。与ING5发挥肿瘤抑制作用一致，ING5基因敲除小鼠在18个月大时发生生发中心弥漫性大B细胞淋巴瘤的几率比对照小鼠高6倍。这些数据表明，ING5在体内发挥作用以维持多个器官中的干细胞特性，干细胞群体的减少并不限制小鼠的寿命，并且与其他ING家族成员的一个子集一样，ING5在体内造血细胞中发挥肿瘤抑制作用。
