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

PLoS Pathog. 2023 Oct 23;19(10):e1011731. doi: 10.1371/journal.ppat.1011731. eCollection 2023 Oct.

Abstract

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.

MeSH terms

  • Animals
  • Cholesterol / metabolism
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Histones / metabolism
  • Macrophages / metabolism
  • Mice
  • Mycobacterium tuberculosis* / metabolism
  • Sirtuins* / genetics
  • Sirtuins* / metabolism

Substances

  • Cholesterol
  • Histones
  • Sirt6 protein, mouse
  • Sirtuins
  • Histone-Lysine N-Methyltransferase

Grants and funding

This work was supported by funds from the Department of Biotechnology (BT/PR41341/MED/29/1535/2020 DT. 13.08.2021; DBT No. BT/PR27352/BRB/10/1639/2017, DT.30/8/2018 and BT/PR13522/COE/34/27/2015, DT.22/8/2017 to K.N.B) and the Department of Science and Technology (DST, EMR/2014/000875, DT.4/12/15 to K.N.B.), New Delhi, India. K.N.B. thanks Science and Engineering Research Board (SERB), DST, for the award of J. C. Bose National Fellowship (JBR/2021/000011 and SB/S2/JCB-025/2016). K.N.B. also acknowledges the funding (SP/DSTO-19-0176, DT.06/02/2020) from SERB. The authors thank DST-FIST, UGC Centre for Advanced Study and DBT-IISc Partnership Program (Phase-II at IISc BT/PR27952/INF/22/212/2018), Institute of Eminence (IoE) support of IISc (IE/REDA-23-1757) for the funding and infrastructure support. Fellowships were received from IISc (P.P., G.K.L., and T.M.), UGC (B.B.) and Prime Minister’s Research Fellowship (PMRF) (A.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.