Transcriptomic profiling of healthy individual-derived LCLs revealed inter-individual variability towards-hypoxia-responsive pathways

Abstract

AbstractHypoxia, or low oxygen levels, affects various developmental, physiological, and pathological processes. It’s been consistently reported that there is an inter-individual variability at genetic and molecular pathways related to oxygen sensing and response. Understanding the underlying variability towards hypoxia sensing and response in health and disease conditions is challenging. ThePrakritistratification method of Ayurveda offers solutions, which classifies healthy individuals into different groups based on multisystem phenotyping. Our lab has previously used this method and provided evidence for the variability in hypoxia responsiveness physiologically among healthy individuals at population levels.Our current study seeks to understand hypoxia sensing and response pathways at cellular levels. We used eight Lymphoblastoid cell lines (LCLs) developed from healthy individuals of extremePrakrititypes. Hypoxia challenge experiments were performed using 0.2% oxygen for 24 and 48 hrs. of chronic hypoxia and captured global transcriptomics profiles. Differentially expressed genes revealed activation of core hypoxia-induced transcriptomic signatures, such as HIF-1⍺ signaling and their metabolic reprogramming in pooled as well as in all Prakriti groups. However, there werePrakriti-specific differences, such as activation of TGF-β mediated ROS and PI3K/AKT/mTOR driven mTORC1complex in Kapha, downregulation of cholesterol homeostasis and regulation of Phosphoinositide biosynthesis in membrane potential observed in the Pitta group. In contrast, ER stress-induced activation of cell survival response via Unfolded protein response in the Vata group. ThePrakritistratification method will provide a novel method to understand inter-individual differences in hypoxia response pathways.SignificanceHypoxia can significantly impact various aspects of our health and well-being. All nucleated cells sense and respond to hypoxia, depending upon their cellular and metabolic activities. Its wide utility and spatiotemporal regulation make it a crucial target to study. We have used thePrakritistratification method of Ayurveda to explore hypoxia sensing and response at cellular levels. Lymphoblastoid Cell Lines (LCLs) developed from the peripheral blood of stratified healthy individuals have been utilized to study the expression level variability at the baseline and hypoxia-induced conditions. The outcomes of our study will be crucial to understanding inter-individual variability in response to hypoxia overlayed baseline variations. Resulting in differential susceptibility towards hypoxic response in health and contributes to understanding variable outcomes in disease conditions. Molecular targets from our study will further be utilized for interventional drug targets in hypoxia-induced disease conditions.