Identification of a miRNA–mRNA Regulatory Networks in Placental Tissue Associated With Tibetan High Altitude Adaptation

Noryung Tenzing,Martha Tissot Van Patot,Ri-Li Ge,Zhuoya Wang,Juanli Liu,Huifang Liu,Qiying Xu,Yanjun Wang,Tana Wuren

doi:10.3389/fgene.2021.671119

Noryung Tenzing, Martha Tissot Van Patot + Show 7 more

Open Access

https://doi.org/10.3389/fgene.2021.671119

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Abstract

The Tibetan population has lived and successfully reproduced at high altitude for many generations. Studies have shown that Tibetans have various mechanisms for protection against high-altitude hypoxia, which are probably due, at least in part, to placental adaptation. However, comprehensive in silico analyses of placentas in Tibetans are lacking. We performed a microarray-based comparative transcriptome analysis of 10 Tibetan women from Yushu, Qinghai, CHN (∼3,780 m) and 10 European women living in Leadville, CO, United States (∼3,100 m) for less than three generations. Expression of HIF-1α, STAT3, EGFR, HSP5A, XBP1, and ATF6A mRNA was less in the Tibetan placentas as compared with European placentas. A total of 38 miRNAs were involved in regulating these genes. Differentially expressed genes were enriched for HIF1α signaling pathways, protein processing in the endoplasmic reticulum, PI3K-AKT signaling pathways, and MAPK signaling pathways. Based on the transcriptome profiles, the Tibetan population was distinct from the European population; placental tissues from the Tibetan population are lacking hypoxic responses, and “passivation” occurs in response to hypoxic stress. These results provide insights into the molecular signature of adaptation to high altitudes in these two populations.

Highlights

Mountain areas account for approximately 24% of the Earth’s surface
The hypoxic environment results in more extensive downregulation of mRNAs in Tibetan placentas at high altitudes than in placentas from European women living in highaltitude conditions
There was less hypoxia-inducible factor (HIF)-1α and signal transducer and activator of transcription 3 (STAT3) and greater miR-526b3p in Tibetan compared with European placentas, suggesting blunted responses to hypoxia and stress through miR-526b3p

Summary

Introduction

More than 140 million humans live at high altitude, defined as areas above 2,500 m (8,000 ft) (Yi et al, 2010; Friedrich and Wiener, 2020). The characteristic environmental features of high-altitude regions include low oxygen pressure, low temperature, significant diurnal temperature variation, low humidity, and strong UV radiation (Peacock, 1998; Butaric and Klocke, 2018). Survival at high altitudes is extremely challenging, especially due to the hypoxic conditions. Activation of stress signaling pathways may be beneficial under hypoxic conditions, excessive stress results in apoptosis. Hypoxia can cause oxidative stress, nutrient deficiencies, and suppression of signaling pathways, which interferes with protein folding, and leads to the amassing of misfolded and unfolded proteins, resulting in endoplasmic reticulum (ER) stress (Feldman et al, 2005; Lee et al, 2020)

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