MicroRNA-211 Regulates Oxidative Phosphorylation and Energy Metabolism in Human Vitiligo

Abstract

Vitiligo is a common, chronic skin disorder characterized by loss of epidermal melanocytes and progressive depigmentation. Vitiligo has complex immune, genetic, environmental, and biochemical etiology, but the exact molecular mechanisms of vitiligo development and progression, particularly those related to metabolic control, are poorly understood. Here we characterized the human vitiligo cell line PIG3V and the normal human melanocytes, HEM-l by RNA-sequencing (RNA-seq), targeted metabolomics, and shotgun lipidomics. Melanocyte-enriched miR-211, a known metabolic switch in non-pigmented melanoma cells, was severely downregulated in vitiligo cell line PIG3V and skin biopsies from vitiligo patients, while its predicted targets transcriptional co-activator PGC1-α (PPARGC1A), ribonucleotide reductase regulatory subunit M2 (RRM2), and serine-threonine protein kinase TAO1 (TAOK1) were reciprocally upregulated. miR-211 binds to PGC1-α 3’UTR locus and represses it. Although mitochondrial numbers were constant, mitochondrial complexes I, II, and IV and respiratory responses were defective in vitiligo cells. Nanoparticle-coated miR-211 partially augmented the oxygen consumption rate in PIG3V cells. The lower oxygen consumption rate, changes in lipid and metabolite profiles, and increased reactive oxygen species production observed in vitiligo cells appear to be partly due to abnormal regulation of miR-211 and its target genes. These genes represent potential biomarkers and therapeutic targets in human vitiligo.

Transcriptome stability profiling using 5’-bromouridine IP chase (BRIC-seq) identifies novel and functional microRNA targets in human melanoma cells

“…miR-211 also had a global impact on transcript stability through direct targeting and indirect physiological changes: miR-211 directly targeted and destabilized A375 homeostatic and metabolic processes and indirectly destabilized genes involved in cell cycle, DNA repair, and MYC-dependent regulation. Interestingly, miR-211 destabilized oxidative phosphorylation in A375 cells, a previously described metabolic switch function of miR-211 in melanotic and amelanotic melanomas [36,35,22].…”

“…2E, Fig. 2F) such as oxidative phosphorylation/energy metabolism [34,22,35,36], lipid/fatty acid metabolism [37,36], mitosis/cellcycle progression/cell-cycle checkpoint [38][39][40], and MYC-dependent signaling [41,42], suggesting a miR-211-dependent contribution to half-life dynamics. This altered regulation extended to the individual pathway level, with gene set enrichment analysis (GSEA) for Biocarta pathways showing that integrin signaling, involved in cell shape and mobility, was enriched in destabilized protein-coding transcripts (data not shown), in line with our previous observation of drastically altered shape of A375/211 cells compared to A375 cells [22].…”

Therapeutic Potential of Patient iPSC-Derived iMelanocytes in Autologous Transplantation

“…Greater susceptibility to oxidative stress has been reported in melanocytes from patients with vitiligo compared to those from unaffected individuals, which contributes to melanocyte damage in vitiligo (Jimbow et al, 2001;Maresca et al, 1997). We also identified multiple pathways linked with the oxidative stress response in melanocytes, including oxidative phosphorylation (Sahoo et al, 2017;Spiegelman and Elcheva, 2017), PI3K-AKT signaling (Kim et al, 2017;Shin et al, 2014), and NRF-2 (Shin et al, 2014). Therefore, the RNA sequencing data not only indicate the high similarity in transcriptome characteristics between patient iMels and HEMs but also reveal multiple signaling pathways involved in the pathogenesis of vitiligo.…”

The convergence theory for vitiligo: A reappraisal

“…Consistent differences among cultured melanocytes reveal differences that might define disease progression . For example, abnormal regulation of microRNA‐211 in vitiligo melanocytes can lead to increased reactive oxygen species …”