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.
microRNAs (miRNAs) are well known to be important in mammalian female fertility. However, the genetic regulation of miRNAs associated with female fertility remains largely unknown. Here, we report that two singlenucleotide variants (SNVs) in the miR-23a promoter strongly influence miR-23a transcription and function in granulosa cell (GC) apoptosis. Two novel SNVs, g.-283G>C and g.-271C>T, were detected in the porcine miR-23a promoter by pooled-DNA sequencing. Furthermore, SNVs in the promoter region influenced miR-23a transcription in porcine GCs by altering its promoter activity. Functionally, SNVs in the promoter strongly influenced miR-23a regulation of early apoptosis in porcine GCs cultured in vitro. In addition, a preliminary association analysis showed that the combined genotypes of the two SNVs, rather than a single SNV, were tentatively associated with sow fertility traits in a Large White population. Overall, our findings suggest that the SNVs g.-283G>C and g.-271C>T in the miR-23a promoter are causal variants affecting GC apoptosis and miR-23a may be a potential small-molecule nonhormonal drug for regulating female fertility.
MicroRNA-23a (miR-23a) is an endogenous small activating RNA (saRNA) involved in ovarian granulosa cell (GC) apoptosis and sow fertility by activating lncRNA NORHA transcription. Here, we reported that both miR-23a and NORHA were repressed by a common transcription factor MEIS1, which forms a small network regulating sow GC apoptosis. We characterized the pig miR-23a core promoter, and the putative binding sites of 26 common transcription factors were detected in the core promoters of both miR-23a and NORHA. Of them, transcription factor MEIS1 expression was the highest in the ovary, and widely distributed in various ovarian cells, including GCs. Functionally, MEIS1 is involved in follicular atresia by inhibiting GC apoptosis. Luciferase reporter and ChIP assays showed that transcription factor MEIS1 represses the transcription activity of miR-23a and NORHA through direct binding to their core promoters. Furthermore, MEIS1 represses miR-23a and NORHA expression in GCs. Additionally, MEIS1 inhibits the expression of FoxO1, a downstream of the miR-23a/NORHA axis, and GC apoptosis by repressing the miR-23a/NORHA axis. Overall, our findings point to MEIS1 as a common transcription repressor of miR-23a and NORHA, and develop the miR-23a/NORHA axis into a small regulatory network regulating GC apoptosis and female fertility.
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