Different Erythrocyte MicroRNA Profiles in Low- and High-Altitude Individuals

Abstract

Background: The number of red blood cells (RBCs) increases significantly in response to high-altitude hypoxic environments, and the RBC microRNA (miRNA) expression pattern is similar to that in whole blood. Studies have shown that miRNA in plasma can act as a circulating hypoxia-associated marker, but the effect of a high-altitude hypoxic environment on RBC-derived miRNAs has not yet been reported.Methods: Blood samples were collected from 20 Han Chinese individuals residing at 500 m (Sichuan Han), 10 migrant Han Chinese citizens residing at 3,658 m (Tibet Han) and 12 native Tibetans, and RBC indices measurements and miRNA sequencing analyses were performed for the three sample groups. The levels of some markedly altered miRNAs at high altitude were subsequently measured from 5 randomly selected samples of each group by real-time PCR. Bioinformatic analyses was performed to determine the potential target genes of selected hypoxia-associated miRNAs.Results: Marked changes of several RBC indices were observed among the Tibet Han population, the Tibetan population and the Sichuan Han population. A total of 516 miRNAs derived from RBCs were initially identified by miRNA sequencing in the three sample groups. Compared with the Sichuan Han population, 49 miRNAs were differentially expressed in the Tibet Han population (17 upregulated and 32 downregulated). 12 upregulated and 21 downregulated miRNAs were observed in the Tibetan population compared with the Sichuan Han population. A total of 40 RBC miRNAs were differentially expressed in the Tibetan population (15 upregulated and 25 downregulated) compared with the Tibet Han population. Two significantly altered miRNAs with the highest expression levels (miRNA-144-5p and miR-30b-5p) were selected for real-time PCR analysis, and the results were consistent with those of miRNA sequencing. Furthermore, bioinformatic analyses showed that some potential target genes of miR-144-5p and miR-30b-5p are involved in the erythroid- hypoxia-, and nitric oxide (NO)-related signaling pathways in response to hypoxia.Conclusion: Our findings provide clear evidence, for the first time, that a high-altitude hypoxic environment significantly affects human RBC miRNA profiles.

The OxymiR response to oxygen limitation: a comparative microRNA perspective

“…Of the 516 RBC-derived miRNAs analysed, 49 were found to be differentially expressed (17 up-regulated and 32 downregulated) between low-altitude Sichuan Hans and high-altitude migrant Tibetan Hans. Slightly fewer differential miRNA changes were identified between native high-altitude Tibetans and the low-altitude Sichuan Hans population (12 up-regulated and 21 down-regulated) (Sun et al, 2018).…”

“…Although modest rises in RBC and hemoglobin levels are beneficial in hypoxic high-altitude environments, profound pathological increases elevate blood viscosity and aggravate cellular anoxia, leading to multiple organ dysfunction (Villafuerte and Corante, 2016). Given that erythropoiesis is known to be regulated by miRNAs, studying RBC-derived miRNAs at high altitudes could identify potential miRNA-mediated mechanisms involved in hypoxic adaptations (Felli et al, 2005;Sun et al, 2015Sun et al, , 2018. Below are findings from a study that examined RBC-derived miRNAs from three populations in the Tibet Plateau: (1) native low-altitude Sichuan Han Chinese (residing at ∼500 m), (2) high-altitude native Tibetans (residing at ∼3658 m), and (3) high-altitude migrant Tibet Han (residing at ∼3658 m).…”

Red Blood Cells as Potential Repositories of MicroRNAs in the Circulatory System

“…MiR-320 downregulation has been correlated with the upregulation of the CD71 protein (a key protein in the terminal differentiation process of reticulocytes) in erythrocytes from patients with sickle cell anemia (Chen et al, 2008). Our recent study showed that RBC miR-144-5p and miR-30b-5p are affected by high-altitude hypoxia (Sun et al, 2018). It has also been demonstrated that the expression level of miR-451 in RBCs is associated with the occurrence of chronic mountain sickness (Wang et al, 2015).…”

“…Another study documented that miR-4732-3p within the erythroid-enriched miR-144/451 locus exhibits a high abundance in erythrocytes and targets two critical components (i.e., SMAD2 and SMAD4) of the transforming growth factor beta (TGF-β) pathway that is implicated in erythropoiesis, suggesting that miR-4732-3p plays an important role in promoting cell proliferation during erythroid differentiation (Choi et al, 2005;Masaki et al, 2007;Randrianarison-Huetz et al, 2010). Our team was the first to find that erythrocyte-derived miR-144-5p is affected by highaltitude hypoxic environments and may play a role in erythrocyte production (Sun et al, 2018). Based on the above analysis of miRNAs in RBCs, we proposed that a number of important miRNAs are involved in erythropoiesis.…”

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

“…In another study, mir-142 was shown to directly target HIF1α [81]. Although more research is required to unambiguously link mir-142, HIF1α, and the shape of the RBCs, other studies are available reporting HIF's participation in the regulation of micro-RNAs involved in different stages of erythropoiesis [82][83][84][85] (Table1).…”