Cell-specific gene expression plasticity in response to hypoxia promotes high-altitude adaptive evolution

Area of Science:

• Evolutionary biology
• Molecular biology
• Physiology

Background:

• The interplay between phenotypic plasticity and genetic adaptation is a key evolutionary question.
• Molecular mechanisms linking plasticity and adaptation, especially during environmental change like hypoxia, remain underexplored.
• Sheep were used as a model organism to investigate cellular responses to hypoxia.

Purpose of the Study:

• To explore cell-specific gene expression plasticity and its reversal by genetic adaptation.
• To identify molecular networks and cellular changes involved in hypoxia acclimatization.
• To investigate the role of cellular plasticity in hypoxia-related diseases.

Main Methods:

• Conducted a plain-to-plateau animal translocation experiment with sheep.
• Generated 27 scRNA-seq and 54 snRNA-seq datasets from brain, heart, and lung tissues.
• Analyzed gene expression in over 236,000 cells and 900,000 nuclei.

Main Results:

• Revealed cell-specific gene expression plasticity that is largely reversed by genetic adaptation.
• Identified immune cells as having high reversing plasticity, promoting adaptation through selection.
• Discovered a common regulatory network (AP-1→HIF∣-BHLHE41) underlying cellular plasticity in response to hypoxia.
• Observed cell plasticity, including microglial activation and endothelial-to-mesenchymal transition, across organs.

Conclusions:

• Cellular expression plasticity is a key feature of hypoxia acclimatization, driven by specific regulatory networks.
• Immune cell plasticity plays a crucial role in facilitating genetic adaptation to environmental stressors.
• Understanding cellular responses to hypoxia provides insights into the incidence and progression of related diseases.