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

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 KLF4, BCL6B, EGR1, EPAS1, SMAD6, SMAD7, KDR, ATOH8, and CCN1 genes as potential regulators of hypoxia adaption. We found that KLF4 and EGR1 genes might simultaneously regulate the BCL6B gene, forming a KLF4–EGR1–BCL6B complex. This complex, dominated by KLF4, 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 KLF4–EGR1–BCL6B 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.

Comparative Transcriptome Analyses of Gayal (Bos frontalis), Yak (Bos grunniens), and Cattle (Bos taurus) Reveal the High-Altitude Adaptation

“…In addition, to better understand the hypoxia adaptation of species, we also collected a set of known or potential high-altitude adaptation candidate genes from previously published literature (Zhang et al, 2014;Wang et al, 2016;Peng et al, 2017). clarify the regulatory relationship between genes and identify important hub genes based on gene expression profiles to explore the mechanism of hypoxia adaptation (Wang et al, 2021). Therefore, to further identify the relevant regulatory gene modules related to the functions of each tissue and explore the core driver genes, we used the CPM values of filtered genes to perform WGCNA analysis on three species, respectively (Langfelder and Horvath, 2008).…”

Atonal homolog 8/Math6 regulates differentiation and maintenance of skeletal muscle

“…The transition of fast-twitch fibers to slow-twitch fibers sustained these mice in adapting to hypoxia. Recently, another group studying genes involved in hypoxia has identified Atoh8 as a potential regulator of hypoxia in Tibetan pigs (Wang et al, 2021). At the same time, this study also proposed that Atoh8 has the ability to modulate TGF-β and Akt/mTOR pathways.…”

Plateau Adaptation Gene Analyses Reveal Transcriptomic, Proteomic, and Dual Omics Expression in the Lung Tissues of Tibetan and Yorkshire Pigs

“…TP, as a plateau-adapted breed, are better at adapting to plateau hypoxia than YY [ 26 ]. Many scholars have also conducted important comparisons between different breeds in order to investigate evolutionary patterns and energy metabolism [ 27 ] and the important functional roles of the genes between the different breeds [ 28 ]. The lung and cardiovascular tissues of TP have been shown to have unique advantages against the low oxygen of the plateau [ 29 , 30 ].…”