Li Nian, Yun Bing, Zeng Liqing, Lv Yuanyuan, Zhou Yinqi, Fang Ming, Li Shuo, Chen Yongcai, Huang Enyuan, Zhang Liuhong, Jiang Yao, Zhang Hao, Li Jiaqi, Yuan Xiaolong
Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China.
School of Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, WA, 6149, Australia.
Commun Biol. 2024 Oct 2;7(1):1246. doi: 10.1038/s42003-024-06960-6.
LncRNAs are highly implicated in oxidative stress (OS) during the growth of mammalian follicles. TAK1 binding protein 2 gene (TAB2) has been suggested to involve in the normal apoptosis and proliferation of granulosa cells (GCs), the main supporting cells in ovarian follicles. In this study, we found that TAB2 increased the expressions of SOD1, P50, and P65 to suppress the OS, thereby inhibiting the apoptosis and promoting the proliferation in GCs. Notably, DNMTs appeared to mediate the expression of TAB2 without the changes of DNA methylation at TAB2's promoter. We identified an antisense lncRNA of TAB2, discovered that DNA methylation regulated the transcription of TAB2-AS in GCs, and found TAB2-AS medicated the follicular growth of ovaries in vivo. Mechanistically, the hypomethylation of the CpG site (-1759/-1760) activated the transcription of TAB2-AS, and the 1-155 nt and 156-241 nt of TAB2-AS were respectively complementary to 4368-4534 nt and 4215-4300 nt of TAB2's mRNA to increase the expression of TAB2. Moreover, TAB2-AS inhibited the OS and apoptosis of GCs, while promoted the proliferation of GCs to expedite the follicular growth, which was in line with that of TAB2. Collectively, these findings revealed the antisense lncRNA mechanism mediated by DNA methylation, and TAB2-AS might be the target to control OS during follicular growth in mammals.
长链非编码RNA（LncRNAs）在哺乳动物卵泡生长过程中与氧化应激（OS）密切相关。TAK1结合蛋白2基因（TAB2）被认为参与了颗粒细胞（GCs）的正常凋亡和增殖，颗粒细胞是卵巢卵泡中的主要支持细胞。在本研究中，我们发现TAB2通过增加超氧化物歧化酶1（SOD1）、P50和P65的表达来抑制氧化应激，从而抑制颗粒细胞凋亡并促进其增殖。值得注意的是，DNA甲基转移酶（DNMTs）似乎介导了TAB2的表达，而TAB2启动子处的DNA甲基化并未发生变化。我们鉴定出TAB2的一个反义长链非编码RNA，发现DNA甲基化调节颗粒细胞中TAB2-AS的转录，并发现TAB2-AS在体内介导卵巢卵泡的生长。机制上，CpG位点（-1759/-1760）的低甲基化激活了TAB2-AS的转录，并且TAB2-AS的1-155 nt和156-241 nt分别与TAB2 mRNA的4368-4534 nt和4215-4300 nt互补，从而增加TAB2的表达。此外，TAB2-AS抑制颗粒细胞的氧化应激和凋亡，同时促进颗粒细胞增殖以加速卵泡生长，这与TAB2的作用一致。总的来说，这些发现揭示了由DNA甲基化介导的反义长链非编码RNA机制，并且TAB2-AS可能是控制哺乳动物卵泡生长过程中氧化应激的靶点。
