High-Altitude Stress Orchestrates mRNA Expression and Alternative Splicing of Ovarian Follicle Development Genes in Tibetan Sheep.

Abstract

Simple SummaryTo achieve optimal growth performance and improved fertility in animals living on high plateaus, it is important to understand how high-altitude stress reduces fertility in females. This study analyzed the transcriptome dynamics of Tibetan sheep ovaries under high-altitude stress. High-altitude stress suppressed the expression of follicular development marker genes and impaired the luteinizing hormone/follicle-stimulating hormone signaling pathway. High-altitude stress also increased abnormally spliced isoforms of transcription factors and RNA processing factors. Therefore, high-altitude stress may reduce the fertility of Tibetan sheep by disrupting the normal expression/hormone signaling of follicular development genes. Further work is needed to decipher whether this phenomenon is a unique feature of Tibetan sheep or a general mechanism in animals under high-altitude stress.High-altitude stress threatens the survival rate of Tibetan sheep and reduces their fertility. However, the molecular basis of this phenomenon remains elusive. Here, we used RNA-seq to elucidate the transcriptome dynamics of high-altitude stress in Tibetan sheep ovaries. In total, 104 genes were characterized as high-altitude stress-related differentially expressed genes (DEGs). In addition, 36 DEGs contributed to ovarian follicle development, and 28 of them were downregulated under high-altitude stress. In particular, high-altitude stress significantly suppressed the expression of two ovarian lymphatic system marker genes: LYVE1 and ADAMTS-1. Network analysis revealed that luteinizing hormone (LH)/follicle-stimulating hormone (FSH) signaling-related genes, such as EGR1, FKBP5, DUSP1, and FOS, were central regulators in the DEG network, and these genes were also suppressed under high-altitude stress. As a post-transcriptional regulation mechanism, alternative splicing (AS) is ubiquitous in Tibetan sheep. High-altitude stress induced 917 differentially alternative splicing (DAS) events. High-altitude stress modulated DAS in an AS-type-specific manner: suppressing skipped exon events but increasing retained intron events. C2H2-type zinc finger transcription factors and RNA processing factors were mainly enriched in DAS. These findings revealed high-altitude stress repressed ovarian development by suppressing the gene expression of LH/FSH hormone signaling genes and inducing intron retention of C2H2-type zinc finger transcription factors.