AUTHOR=Wang Tao , Guo Yuanyuan , Liu Shengwei , Zhang Chaoxin , Cui Tongyan , Ding Kun , Wang Peng , Wang Xibiao , Wang Zhipeng 

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

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.628192

DOI=10.3389/fgene.2021.628192

ISSN=1664-8021

ABSTRACT=<p>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. However, the genetic mechanism underlying this adaptation remains elusive. Here, based on multitissue 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 three-node network motifs. We found that among the six tissues (muscle, liver, heart, spleen, kidneys, and lungs), lung tissue may be the key organs for Tibetan pigs to adapt to hypoxic environment. In the lung tissue of Tibetan pigs, we identified <italic>KLF4</italic>, <italic>BCL6B</italic>, <italic>EGR1</italic>, <italic>EPAS1</italic>, <italic>SMAD6</italic>, <italic>SMAD7</italic>, <italic>KDR</italic>, <italic>ATOH8</italic>, and <italic>CCN1</italic> genes as potential regulators of hypoxia adaption. We found that <italic>KLF4</italic> and <italic>EGR1</italic> genes might simultaneously regulate the <italic>BCL6B</italic> gene, forming a <italic>KLF4–EGR1–BCL6B</italic> complex. This complex, dominated by <italic>KLF4</italic>, may enhance the hypoxia tolerance of Tibetan pigs by mediating the TGF-β signaling pathway. The complex may also affect the PI3K-Akt signaling pathway, which plays an important role in angiogenesis caused by hypoxia. Therefore, we postulate that the <italic>KLF4–EGR1–BCL6B</italic> complex may be beneficial for Tibetan pigs to survive better in the hypoxia environments. Although further molecular experiments and independent large-scale studies are needed to verify our findings, these findings may provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals.</p>