KLF4, a Key Regulator of a Transitive Triplet, Acts on the TGF-β Signaling Pathway and Contributes to High-Altitude Adaptation of Tibetan Pigs

Abstract

Background: Tibetan pigs are native mammalian species on the Tibetan Plateau that have evolved distinct physiological traits that allow them to tolerate high-altitude hypoxic environments. They can be used as a suitable animal model for exploring the molecular mechanism of hypoxia adaptation in high-altitude organisms.Results: Here, based on multi-tissue transcriptional data from high-altitude Tibetan pigs and low-altitude Rongchang pigs, we performed a weighted correlation network analysis (WGCNA) and identified key modules related to these tissues. Complex network analysis and bioinformatics analysis were integrated to identify key genes and size-3 network motifs. The results showed that compared to other tissues, the lungs of Tibetan pigs and Rongchang pigs are more significantly different, showing more adaptive transcriptional changes. In the lung tissues of Tibetan pigs, we identified KLF4, BCL6B, EGR1, EPAS1, SMAD6, SMAD7, KDR, ATOH8 and CCN1 genes as potential regulators of hypoxia adaption. We found that KLF4 and EGR1 genes simultaneously regulate the BCL6B gene, forming a KLF4-EGR1-BCL6B transitive triplet. This transitive triplet, dominated by KLF4, may enhance the hypoxia adaptability of Tibetan pigs by mediating the TGF-β signaling pathway. This triplet also regulates the KDR gene, which is involved in the PI3K-Akt signaling pathway and plays an important role in hypoxia adaptation. Conclusions: We postulate that the KLF4-EGR1-BCL6B transitive triplet may contribute to the adaptation of Tibetan pigs to hypoxic environments. These findings provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals.

Evaluation of genes and molecular pathways involved in the development of cardiovascular disease in preeclampsia patients: biological system and bioinformatics analysis approach

“…Also, the MAPK signaling pathway increases the expression of adhesion molecules and ET-1, and decreases NO expression by decreasing PI3K / eNOS signaling. Hypertension is also a consequence of increased expression of ET-1 and adhesion molecules due to resistance arterioles (23,24). In the study by Eyries et On the other hand, MDM2 in the downstream of the PHLPP1 / Nrf2 / MdM2 / FOXO1 signaling pathway can also lead to renal cell apoptosis.…”