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The long noncoding RNA MALAT1 suppresses miR‐211 to confer protection from ultraviolet‐mediated DNA damage in vitiligo epidermis by upregulating sirtuin 1 *
Author(s) -
Brahmbhatt H.D.,
Gupta R.,
Gupta A.,
Rastogi S.,
Misri R.,
Mobeen A.,
Ghosh A.,
Kothari P.,
Sitaniya S.,
Scaria V.,
Singh A.
Publication year - 2021
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.19666
Subject(s) - vitiligo , biology , dna damage , cancer research , microrna , keratinocyte , epidermis (zoology) , pyrimidine dimer , sirtuin 1 , skin cancer , microbiology and biotechnology , downregulation and upregulation , gene , dna , immunology , genetics , cancer , cell culture , anatomy
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.