Long noncoding RNA MALAT1 releases epigenetic silencing of HIV-1 replication by displacing the polycomb repressive complex 2 from binding to the LTR promoter.

Di Qu,Wei-Wei Sun,Li Ma,Taisheng Li,Jian-Hua Wang,Wei Hou,Xia Jin,Li Sun,Li Li

doi:10.1093/nar/gkz117

Abstract

Long noncoding RNAs (lncRNAs) may either repress or activate HIV-1 replication and latency; however, specific mechanisms for their action are not always clear. In HIV-1 infected CD4+ T cells, we performed RNA-Sequencing (RNA-Seq) analysis and discovered an up-regulation of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), an lncRNA previously described in cancer cells that associate with cancer pathogenesis. Moreover, we found that MALAT1 promoted HIV-1 transcription and infection, as its knockdown by CRISPR/Cas9 markedly reduced the HIV-1 long terminal repeat (LTR)-driven gene transcription and viral replication. Mechanistically, through an association with chromatin modulator polycomb repressive complex 2 (PRC2), MALAT1 detached the core component enhancer of zeste homolog 2 (EZH2) from binding with HIV-1 LTR promoter, and thus removed PRC2 complex-mediated methylation of histone H3 on lysine 27 (H3K27me3) and relieved epigenetic silencing of HIV-1 transcription. Moreover, the reactivation of HIV-1 stimulated with latency reversal agents (LRAs) induced MALAT1 expression in latently infected cells. Successful combination antiretroviral therapy (cART) was accompanied by significantly diminished MALAT1 expression in patients, suggesting a positive correlation of MALAT1 expression with HIV-1 replication. Our data have identified MALAT1 as a promoter of HIV-1 transcription, and suggested that MALAT1 may be targeted for the development of new therapeutics.

Highlights

HIV-1 depends on host machineries for completing its life cycle [1,2,3,4]
We first examined whether HIV-1 can regulate the expression of MALAT1 by performing RNA-seq analysis in HIV1-NL4-3-infected and uninfected CD4+ T cells (H9 cell), as described in ‘Materials and methods’ section
The double knockdown of MALAT1 and enhancer of zeste homolog 2 (EZH2) resulted in rescued replication of HIV-1 NL4-3 (Figure 5H). These results demonstrate that MALAT1 promotes HIV-1 replication by antagonizing EZH2-mediated silencing of viral gene transcription

Summary

Introduction

Long noncoding RNAs (LncRNAs) are a new class of host factors that attracted much attention recently. These are the most abundant type of noncoding RNAs, with more than 200 nucleotides in length, and they have been implicated in various physiological and pathological processes, such as epigenetic control of gene expression, chromatin organization, genomic imprinting, immune regulation, cell differentiation and development, viral pathogenesis and oncogenesis [5,6,7,8,9,10,11,12,13]. The mechanism of its action is forming the small nuclear ribonucleoprotein complex (snRNP) in association with several proteins including the double-stranded RNA-binding protein HEXIM1 (hexamethylene bisacetamide induced protein 1) and HEXIM2, MEPCE (methyl-phosphate capping enzyme) and LARP7

Methods

Results

Conclusion