The long noncoding RNA MALAT1 suppresses miR‐211 to confer protection from ultraviolet‐mediated DNA damage in vitiligo epidermis by upregulating sirtuin 1*

Abstract

Summary Background The absence of melanocytes poses a challenge for long‐term tissue homeostasis in vitiligo. Surprisingly, while individuals with Fitzpatrick phototypes I–II (low melanin content) have a higher incidence of melanoma and nonmelanoma skin cancer, people with vitiligo are at a decreased risk for the same. Objectives To understand the molecular mechanisms that protect vitiligo skin from ultraviolet (UV)‐induced DNA damage by (i) characterizing differentially expressed microRNAs in lesional vs. nonlesional epidermis and (ii) identifying their upstream regulators and downstream gene targets. Methods Genome‐wide microRNA profiling of nonlesional and lesional epidermis was performed on five individuals with stable nonsegmental vitiligo using next‐generation RNA sequencing. The relevance of the upstream regulator and downstream target gene of the most differentially expressed microRNA was studied. Results Our study found sirtuin1 (SIRT1), an NAD‐dependent deacetylase, to be a direct target of miR‐211 – the most significantly downregulated microRNA in lesional epidermis. Inhibition of SIRT1 with EX‐527 downregulated keratin 10 and involucrin, suggesting that SIRT1 promotes keratinocyte differentiation. Overexpression of miR‐211 mimic led to a significant increase in γ‐H2AX positivity and cyclobutane pyrimidine dimer (CPD) formation, hallmarks of UVB‐mediated DNA damage. These effects could be ameliorated by the addition of resveratrol, a SIRT1 activator. Furthermore, a long noncoding RNA, MALAT1, was identified as a negative upstream regulator of miR‐211. Overexpression of MALAT1 resulted in increased expression of SIRT1 and a concomitant removal of UVB‐induced CPDs in primary keratinocytes. Conclusions These findings establish a novel MALAT1–miR‐211–SIRT1 signalling axis that potentially confers protection to the ‘amelanotic’ keratinocytes in vitiligo.

microRNAs in the Regulation of Melanogenesis

“…Therefore, while the role of inflammation in modulating cell behavior and the signaling pathways involved in skin pigmentation is beginning to be elucidated [ 6 ], further investigation concerning miRNAs involved in skin inflammation might be helpful. In addition, based on increasing knowledge on the relationship between different classes of non-coding RNAs, new relevant information is expected from studies concerning the interaction and reciprocal regulation of miRNAs and other non-coding RNA classes [ 14 , 98 ]. In conclusion, increasing evidence shows the involvement of miRNAs in melanogenesis and skin pigmentation disorders.…”

Regulatory noncoding RNAs help protect keratinocytes from ultraviolet‐mediated damage in vitiligo

“…The findings of Brahmbhatt et al . shift the focus to NSV keratinocytes and DNA damage 3 . Interestingly, in keratinocytes, miR‐211 activity appears to be dependent on the presence of lncRNA MALAT1.…”

“…2 In this issue of the BJD, Brahmbhatt et al reveal a molecular mechanism in lesional vitiligo keratinocytes that may account for this observation, which protects keratinocytes from ultraviolet (UV)-induced DNA damage. 3 The authors studied RNA in lesional and nonlesional epidermal vitiligo skin biopsies in five patients. They focused on two classes of noncoding RNAs (ncRNA) that play important roles in the regulation of gene expression in cells: 4 microRNAs (miRNAs), which interact with binding sites on target mRNAs and repress their expression; and long ncRNAs (lncRNAs), which are frequently involved in epigenetic gene regulation.…”

“…6 The findings of Brahmbhatt et al shift the focus to NSV keratinocytes and DNA damage. 3 Interestingly, in keratinocytes, miR-211 activity appears to be dependent on the presence of lncRNA MALAT1. The authors show that MALAT1 harbours a functional miR-211 binding site and represses miR-211.…”

“…For patients with NSV, while future clinical studies are needed to show these findings have clinical benefit, these data offer a biologically plausible explanation for the observed risk reduction in KSC reported. 2 C. Cotter iD , 1 M. Kretz iD 2 and N. Rajan iD 3,4 The importance of keratinocyte-dendritic cell interactions in understanding fragrance allergy Fragrance allergy is one of the most common causes of allergic contact dermatitis, 1 and affected individuals report a reduced quality of life. 2 Compounds with low sensitizing potency can be activated abiotically, through air oxidation, or, biotically, through enzyme activity in the skin to generate allergens.…”