Epigenetic Promoter DNA Methylation of miR-124 Promotes HIV-1 Tat-Mediated Microglial Activation via MECP2-STAT3 Axis

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Palsamy PeriyasamyShilpa Buch

Abstract

The present study demonstrates HIV-1 Tat-mediated epigenetic downregulation of microglial miR-124 and its association with microglial activation. Exposure of mouse primary microglia isolated from newborn pups of either sex to HIV-1 Tat resulted in decreased expression of primary miR-124-1, primary miR-124-2 as well as the mature miR-124. In parallel, HIV-1 Tat exposure to mouse primary microglial cells resulted in increased expression of DNA methylation enzymes, such as DNMT1, DNMT3A, and DNMT3B, which were also accompanied by increased global DNA methylation. Bisulfite-converted genomic DNA sequencing in the HIV-1 Tat-exposed mouse primary microglial cells further confirmed increased DNA methylation of the primary miR-124-1 and primary miR-124-2 promoters. Bioinformatic analyses identified MECP2 as a novel 3'-UTR target of miR-124. This was further validated in mouse primary microglial cells wherein HIV-1 Tat-mediated downregulation of miR-124 resulted in increased expression of MECP2, leading in turn to further repression of miR-124 via the feedback loop. In addition to MECP2, miR-124 also modulated the levels of STAT3 through its binding to the 3'-UTR, leading to microglial activation. Luciferase assays and Ago2 immunoprecip...Continue Reading

Citations

Mar 29, 2019·Nature Reviews. Immunology·Qian Zhang, Xuetao Cao
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Nov 12, 2019·Frontiers in Cellular and Infection Microbiology·Clementine WalletChristian Schwartz
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Oct 27, 2020·Epigenetics : Official Journal of the DNA Methylation Society·Mayur DokeThangavel Samikkannu
Mar 16, 2019·Brain, Behavior, and Immunity·Palsamy PeriyasamyShilpa Buch
Apr 2, 2021·Neuroscience Letters·Susmita SilShilpa Buch
Feb 26, 2021·JCI Insight·Wouter A van der HeijdenQuirijn de Mast
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Aug 25, 2021·Current HIV/AIDS Reports·Susmita SilShilpa Buch
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