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G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival

Prakhar, P and Bhatt, B and Lohia, GK and Shah, A and Mukherjee, T and Kolthur-Seetharam, U and Sundaresan, NR and Rajmani, RS and Balaji, Balaji (2023) G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. In: PLoS Pathogens, 19 (10).

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Official URL: https://doi.org/10.1371/journal.ppat.1011731


Cholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that the coordinated action of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and SIRT6 (H3K9 deacetylase) orchestrate cholesterol build-up in in vitro and in vivo mouse models of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while SIRT6 along with G9a represses the genes involved in cholesterol efflux. The accumulated cholesterol in Mtb infected macrophages promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9a in vitro and pharmacological inhibition in vivo; or utilization of BMDMs derived from Sirt6�/� mice or in vivo infection in haplo-insufficient Sirt6�/+ mice; hampered host cholesterol accumulation and restricted Mtb burden. These findings shed light on the novel roles of G9a and SIRT6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival. © 2023 Prakhar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Item Type: Journal Article
Publication: PLoS Pathogens
Publisher: Public Library of Science
Additional Information: The copyright for this article belongs to author.
Keywords: cholesterol; histone lysine methyltransferase; sirtuin 6; small interfering RNA; cholesterol; histone; Sirt6 protein, mouse; sirtuin, animal experiment; animal model; Article; bone marrow derived macrophage; chemoluminescence; cholesterol synthesis; chromatin immunoprecipitation; colony forming unit; controlled study; drug accumulation; female; flow cytometry; fluorescence microscopy; gene expression; genetic transfection; histone modification; immunoblotting; immunofluorescence; immunoprecipitation; macrophage; male; microtomy; MTT assay; mycobacteriosis; Mycobacterium tuberculosis; nonhuman; oxidative stress; peripheral blood mononuclear cell; RAW 264.7 cell line; real time reverse transcription polymerase chain reaction; RNA isolation; survival; animal; genetics; metabolism; mouse; Mycobacterium tuberculosis, Animals; Cholesterol; Histones; Macrophages; Mice; Mycobacterium tuberculosis; Sirtuins
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 04 Mar 2024 09:16
Last Modified: 04 Mar 2024 09:16
URI: https://eprints.iisc.ac.in/id/eprint/84263

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