Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing.
Following entry and reverse transcription, the HIV-1 genome is integrated into the host genome. In contrast to productively infected cells, latently infected cells frequently harbor HIV-1 genomes integrated in heterochromatic structures, allowing persistence of transcriptionally silent proviruses. Microglial cells are the main HIV-1 target cells in the central nervous system and constitute an important reservoir for viral pathogenesis. In the present work, we show that, in microglial cells, the co-repressor COUP-TF interacting protein 2 (CTIP2) recruits a multienzymatic chromatin-modifying complex and establishes a heterochromatic environment at the HIV-1 promoter. We report that CTIP2 recruits histone deacetylase (HDAC)1 and HDAC2 to promote local histone H3 deacetylation at the HIV-1 promoter region. In addition, DNA-bound CTIP2 also associates with the histone methyltransferase SUV39H1, which increases local histone H3 lysine 9 methylation. This allows concomitant recruitment of HP1 proteins to the viral promoter and formation of local heterochromatin, leading to HIV-1 silencing. Altogether, our findings uncover new therapeutic opportunities for purging latent HIV-1 viruses from their cellular reservoirs.
Marban
Céline
C
INSERM unité 575 Pathophysiology of Nervous System, Centre de Neurochimie, Strasbourg, France.
Suzanne
Stella
S
Dequiedt
Franck
F
de Walque
Stéphane
S
Redel
Laetitia
L
Van Lint
Carine
C
Aunis
Dominique
D
Rohr
Olivier
O
D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D020868:Gene Silencing; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011496:Protein Methyltransferases; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication
C479740:BCL11B protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C407843:SUV39H1 protein, human; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases