Wang Siqi, Li Yuqi, Zeng Qiang, Yang Liu, Du Xing, Li Qifa
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
Antioxidants (Basel). 2022 Jun 15;11(6):1174. doi: 10.3390/antiox11061174.
Phenotypes are the result of the interaction between the gene and the environment, so the response of individuals with different genotypes to an environment is variable. Here, we reported that a mutation in miR-23a influences granulosa cells (GCs) response to oxidative stress, a common mechanism of environmental factors affecting female reproduction. We showed that nuclear miR-23a is a pro-apoptotic miRNA in porcine GCs through the activation of the transcription and function of NORHA, a long non-coding RNA (lncRNA) induces GC apoptosis and responses to oxidative stress. Mechanistically, miR-23a acts as an endogenous small activating RNA (saRNA) to alter histone modifications of the NORHA promoter through the direct binding to its core promoter. A C > T mutation was identified at −398 nt of the miR-23a core promoter, which created a novel binding site for the transcription factor SMAD4 and recruited the transcription repressor SMAD4 to inhibit miR-23a transcription and function in GCs. Notably, g.−398C > T mutation in the miR-23a promoter reduced GCs response to oxidative stress. In addition, g.−398C > T mutation was significantly associated with sow fertility traits. In short, our findings preliminarily revealed the genetic basis of individual differences in the response to oxidative stress from the perspective of a single mutation and identified miR-23a as a candidate gene for the environmental adaptation to oxidative stress.
表型是基因与环境相互作用的结果，因此不同基因型的个体对环境的反应是可变的。在此，我们报道miR-23a中的一个突变影响颗粒细胞（GCs）对氧化应激的反应，氧化应激是影响雌性生殖的环境因素的常见机制。我们发现，核内miR-23a是猪颗粒细胞中的一种促凋亡微小RNA，它通过激活NORHA（一种长链非编码RNA（lncRNA），可诱导颗粒细胞凋亡并对氧化应激作出反应）的转录和功能来发挥作用。从机制上讲，miR-23a作为一种内源性小激活RNA（saRNA），通过直接结合NORHA启动子的核心区域来改变其组蛋白修饰。在miR-23a核心启动子的−398 nt处鉴定到一个C>T突变，该突变产生了一个新的转录因子SMAD4结合位点，并招募转录抑制因子SMAD4来抑制颗粒细胞中miR-23a的转录和功能。值得注意的是，miR-23a启动子中的g.−398C>T突变降低了颗粒细胞对氧化应激的反应。此外，g.−398C>T突变与母猪繁殖性状显著相关。简而言之，我们的研究结果从单个突变的角度初步揭示了个体对氧化应激反应差异的遗传基础，并确定miR-23a为氧化应激环境适应性的候选基因。
