The long noncoding RNA MALAT1 suppresses miR‐211 to confer protection from ultraviolet‐mediated DNA damage in vitiligo epidermis by upregulating sirtuin 1*. (1st June 2021)

• Record Type: Journal Article
• Authors: Brahmbhatt, H.D.; Gupta, R.; Gupta, A.; Rastogi, S.; Misri, R.; Mobeen, A.; Ghosh, A.; Kothari, P.; Sitaniya, S.; Scaria, V.; Singh, A.
• Is Part Of: British journal of dermatology. Volume 184:Number 6(2021)
• Page Start: 1132
• Page End: 1142
• Publication Date: 2021-06-01
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.19666
• Languages: English
• ISSNs: 0007-0963

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. Abstract: What is already known about this topic? Ultraviolet B radiation is known to cause DNA damage in keratinocytes. Individuals with Fitzpatrick phototypes I–II and people with albinism are at greater risk for developing melanoma and nonmelanoma skin cancers (NMSCs). Epidemiological studies suggest that individuals with vitiligo have a lower risk of developing melanoma and NMSCs than ethnicity‐matched healthy controls. What does this study add? Our study demonstrates significant downregulation of miR‐211 and consequent upregulation of its target gene SIRT1 in lesional epidermis. The long noncoding RNA MALAT1 is overexpressed in lesional epidermis and it negatively regulates miR‐211, resulting in SIRT1 overexpression. This study demonstrates that a novel MALAT1 –miR‐211–SIRT1 axis confers protection to the 'melanin‐deprived' lesional vitiligo epidermis from ultraviolet‐mediated DNA damage. What is the translational message? Further investigation into the downstream mechanisms of the MALAT1 –miR‐211–SIRT1 axis may enable better understanding of the rewired vitiligo skin, in addition to having important implications in management of skin cancers Linked Comment: Cotter. Br J Dermatol 2021; 184 :999–1000 .