Abstract
The function of alveolar type II epithelial (ATII) cells is severely hampered by oxygen deficiency, and understanding the regulatory mechanisms controlling responses to hypoxia may assist in relieving injury induced by hypoxia. In this study, we cultured ATII cells from Tibetan pigs and Landrace pigs under hypoxic and normoxic environments to screen for differentially expressed (DE) lncRNAs, DEmiRNAs, and construct their associated ceRNA regulatory networks in response to hypoxia. Enrichment analysis revealed that target genes of DElncRNAs of Tibetan pigs and Landrace pig between the normoxic (TN, LN) and hypoxic (TL, LL) groups significantly enriched in the proteoglycans in cancer, renal cell carcinoma, and erbB signaling pathways, while the target genes of DEmiRNAs were significantly enriched in the axon guidance, focal adhesion, and mitogen-activated protein kinase (MAPK) signaling pathways. Hypoxia induction was shown to potentially promote apoptosis by activating the focal adhesion/PI3K-Akt/glycolysis pathway. The ssc-miR-20b/MSTRG.57127.1/ssc-miR-7-5p axis potentially played a vital role in alleviating hypoxic injury by regulating ATII cell autophagy under normoxic and hypoxic conditions. MSTRG.14861.4-miR-11971-z-CCDC12, the most affected axis, regulated numerous RNAs and may thus regulate ATII cell growth in Tibetan pigs under hypoxic conditions. The ACTA1/ssc-miR-30c-3p/MSTRG.23871.1 axis is key for limiting ATII cell injury and improving dysfunction and fibrosis mediated by oxidative stress in Landrace pigs. Our findings provide a deeper understanding of the lncRNA/miRNA/mRNA regulatory mechanisms of Tibetan pigs under hypoxic conditions.
Highlights
The breeding of Tibetan pigs by humans can be traced back to the seventh century, and these animals adapted to hypoxic and low-pressure environments due to long-term natural selection on the Tibetan Plateau [1–3]
Hypoxia induces pulmonary injury via cell apoptosis, which leads to transdifferentiation of alveolar type II epithelial (ATII) cells; the regeneration of ATII cells is an important indicator of hypoxia damage [42]
We found that exposure to hypoxia was mainly associated with the intracellular component Gene Ontology (GO) term, and P4HA1, which could be induced by HIF-1α or hypoxia-independent factors, is a part of a gene expression signature associated with hypoxia and glycolysis in ATII cells [59, 60]
Summary
The breeding of Tibetan pigs by humans can be traced back to the seventh century, and these animals adapted to hypoxic and low-pressure environments due to long-term natural selection on the Tibetan Plateau [1–3]. The regulation of hypoxia-related genes enables cellular adaptation to a hypoxic environment via increased glucose metabolism [11], cell proliferation and migration [12], increased survival [13], as well as by the promotion of angiogenesis [14]. Advances in sequencing technology have revealed mRNA expression levels are regulated by miRNAs, lncRNAs, or circRNAs, and analysis of these factors could provide comprehensive insight into the complicated cellular biological process of hypoxia as a rapid approach to reveal the regulatory network [15, 16]. In Tibetan pigs, mounting research evidence has shown that RNAs are abundantly expressed in the lung tissue transcriptome in response to hypoxia [23], but no integrated analyses of how their networks regulate ATII cells have been performed. We compared the expression levels of mRNAs, miRNAs, and lncRNAs in the ATII cells of Tibetan and Landrace pigs under normoxic and hypoxic conditions.
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