A CRISPR/Cas9 screen identifies the histone demethylase MINA53 as a novel HIV-1 latency-promoting gene (LPG)

Huang, Huachao; Kong, Weili; Jean, Maxime; Fiches, Guillaume; Zhou, Dawei; Hayashi, Tsuyoshi; Que, Jianwen; Santoso, Netty; Zhu, Jian

doi:10.1093/nar/gkz493

Cited by 43 publications

(47 citation statements)

References 65 publications

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“…ChIP assay was conducted as described previously [37,41]. Cells were cross-linked by using 0.5% formaldehyde, followed by treating with 125 mM glycine to quench the reaction.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

Nucleolar protein NOP2/NSUN1 suppresses HIV-1 transcription and promotes viral latency by competing with Tat for TAR binding and methylation

et al. 2020

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Recent efforts have been paid to identify previously unrecognized HIV-1 latency-promoting genes (LPGs) that can potentially be targeted for eradication of HIV-1 latent reservoirs. From our earlier orthologous RNAi screens of host factors regulating HIV-1 replication, we identified that the nucleolar protein NOP2/NSUN1, a m5C RNA methyltransferase (MTase), is an HIV-1 restriction factor. Loss-and gain-of-function analyses confirmed that NOP2 restricts HIV-1 replication. Depletion of NOP2 promotes the reactivation of latently infected HIV-1 proviruses in multiple cell lines as well as primary CD4 + T cells, alone or in combination with latency-reversing agents (LRAs). Mechanistically, NOP2 associates with HIV-1 5' LTR, interacts with HIV-1 TAR RNA by competing with HIV-1 Tat protein, as well as contributes to TAR m5C methylation. RNA MTase catalytic domain (MTD) of NOP2 mediates its competition with Tat and binding with TAR. Overall, these findings verified that NOP2 suppresses HIV-1 transcription and promotes viral latency.

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“…ChIP assay was conducted as described previously [37,41]. Cells were cross-linked by using 0.5% formaldehyde, followed by treating with 125 mM glycine to quench the reaction.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

Nucleolar protein NOP2/NSUN1 suppresses HIV-1 transcription and promotes viral latency by competing with Tat for TAR binding and methylation

et al. 2020

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“…Importantly, loss of these factors did not impair cell viability, suggesting that these genes could be suitable targets for therapeutic intervention [55]. Haung et al also performed a CRISPR KO screen and identified the MINA53 histone demethylase, which promotes HIV latency by demethylating H3K36me3 [52]. Similarly, Rathore et al identified several factors involved in RNA degradation and ubiquitin-mediated proteolysis as HIV-1 latency regulators [54].…”

Section: Discussionmentioning

confidence: 99%

“…Haung et al . also performed a CRISPR KO screen and identified the MINA53 histone demethylase, which promotes HIV latency by demethylating H3K36me3 [ 52 ]. Similarly, Rathore et al .…”

Section: Discussionmentioning

confidence: 99%

“…Our work joins several other CRISPR screens that aimed to identify cell partners for HIV [ 52 – 55 ]. Mechanistically, we found that ZNF304 associates with TRIM28 and potentially recruits heterochromatin-inducing complexes, such as polycomb repressing complex (PRC1/2) and SETB1 histone lysine methyltransferases, to the HIV promoter, thereby depositing H3K27me3, H2AK119Ub and H3K9me3, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide CRISPR knockout screen identifies ZNF304 as a silencer of HIV transcription that promotes viral latency

2020

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Despite the widespread use of anti-retroviral therapy, human immunodeficiency virus (HIV) still persists in an infected cell reservoir that harbors transcriptionally silent yet replicationcompetent proviruses. While significant progress has been made in understanding how the HIV reservoir is established, transcription repression mechanisms that are enforced on the integrated viral promoter have not been fully revealed. In this study, we performed a wholegenome CRISPR knockout screen in HIV infected T cells to identify host genes that potentially promote HIV latency. Of several top candidates, the KRAB-containing zinc finger protein, ZNF304, was identified as the top hit. ZNF304 silences HIV gene transcription through associating with TRIM28 and recruiting to the viral promoter heterochromatin-inducing methyltransferases, including the polycomb repression complex (PRC) and SETB1. Depletion of ZNF304 expression reduced levels of H3K9me3, H3K27me3 and H2AK119ub repressive histone marks on the HIV promoter as well as SETB1 and TRIM28, ultimately enhancing HIV gene transcription. Significantly, ZNF304 also promoted HIV latency, as its depletion delayed the entry of HIV infected cells into latency. In primary CD4 + cells, ectopic expression of ZNF304 silenced viral transcription. We conclude that by associating with TRIM28 and recruiting host transcriptional repressive complexes, SETB1 and PRC, to the HIV promoter, ZNF304 silences HIV gene transcription and promotes viral latency.

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“…In particular, studies have reported the involvement of JMJD10/MINA53 in histone methylation by antagonizing trimethyl lysine 9 on histone H3 (H3K9me3) [7][8][9][10][11][12][13][14][15]. Later studies indicated that JMJD10/MINA53 was also involved in the repression of H3K36me3 [16], H3K27me3, and H4K20me3 [17].…”

Section: Introductionmentioning

confidence: 99%

Molecular Signatures of JMJD10/MINA53 in Gastric Cancer

Aziz

Hong

et al. 2020

Cancers

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The JMJD10 gene and its encoded protein MYC-induced nuclear antigen (MINA53) are associated with multiple cancers. Besides having both an oncogenic and tumor suppressor function, the intricate role of JMJD10 in cancer is complex as it depends on the cancer type. In particular, the functional role of JMJD10/MINA53 in gastric cancer has been poorly understood. In this study, we have unraveled the molecular signatures and functional roles of JMJD10/MINA53 in gastric cancer by multiple approaches, i.e., multi-omics bioinformatics study, analysis of human gastric cancer tissues, and studies in vitro using knockdown or overexpression strategies in gastric cancer cell lines. The results indicated that the JMJD10 gene and MINA53 protein are commonly overexpressed in cancer patients. JMJD10/MINA53 is involved in the regulation of proliferation and survival of gastric cancer by controlling cell cycle gene expression. These processes are highly associated with MINA53 enzymatic activity in the regulation of H3K9me3 methylation status and controlling activation of AP-1 signaling pathways. This highlights the oncogenic role of JMJD10/MINA53 in gastric cancer and opens the opportunity to develop therapeutic targeting of JMJD10/MINA53 in gastric cancer.

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A CRISPR/Cas9 screen identifies the histone demethylase MINA53 as a novel HIV-1 latency-promoting gene (LPG)

Cited by 43 publications

References 65 publications

Nucleolar protein NOP2/NSUN1 suppresses HIV-1 transcription and promotes viral latency by competing with Tat for TAR binding and methylation

Nucleolar protein NOP2/NSUN1 suppresses HIV-1 transcription and promotes viral latency by competing with Tat for TAR binding and methylation

Genome-wide CRISPR knockout screen identifies ZNF304 as a silencer of HIV transcription that promotes viral latency

Molecular Signatures of JMJD10/MINA53 in Gastric Cancer

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