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DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [ONT cDNA sequencing]

ABSTRACT: DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [ONT cDNA sequencing]

PROVIDER: PRJNA1091962 | ENA |

REPOSITORIES: ENA

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DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [ONT cDNA sequencing]

Project description:The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. However, how HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains poorly understood. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding. Simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the independent epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.

2024-03-26 | GSE262483 | GEO

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [ONT whole genome DNA]

2024-03-26 | GSE262482 | GEO

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex

2024-03-26 | GSE242143 | GEO

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [CUT&RUN]

2024-03-26 | GSE240384 | GEO

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [Bulk RNA-seq]

2024-03-26 | GSE240386 | GEO

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [ONT whole genome DNA]

Project description:DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [ONT whole genome DNA]

| PRJNA1092053 | ENA

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex

Project description:DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex

| PRJNA1011851 | ENA

Assessing the impact of the R252W Charcot-Marie-Tooth disease mutation in MORC2 on HUSH-mediated repression

Project description:HeLa cells lacking MORC2 generated through CRISPR/Cas9-mediated gene disruption were reconstituted with either wild-type or R252W mutant MORC2, and re-repression of HUSH target genes assessed by RNA-seq

2017-05-29 | GSE95455 | GEO

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [CUT&RUN]

Project description:DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex [CUT&RUN]

| PRJNA1003476 | ENA

The HUSH-SETDB1-MORC2 epigenetic repressor complex restricts herpesvirus infection in association with PML nuclear bodies

Project description:The establishment of latent herpes simplex virus 1 (HSV-1) infection is controlled by promyelocytic leukemia nuclear bodies (PML NBs). Viral genomes are recruited to PML NBs structures and chromatinized by repressive H3.3K9me3 modified H3.3 histone variant to form viral DNA-containing PML-NBs (vDCP NBs). Exactly how this occurs is unclear. Here we identify an essential role for the HUSH complex and its SETDB1 and MORC2 effectors in the establishment and maintenance of latent herpes simplex virus 1 (HSV-1) infection. ChIP-seq analyses conducted on latently/quiescently infected primary human fibroblasts highlight the association of the H3K9me3 mark with the entire viral genome. We demonstrate the necessity of HUSH, SETDB1, and MORC2 in the establishment of repressive heterochromatin in vDCP NBs. Depletion of these components prior to viral infection results in reduced H3K9me3 levels across the entirety of latent/quiescent HSV-1 genomes, with minimal impact on the cellular genome as a whole. Once latency is established, depletion of HUSH, SETDB1, or MORC2 by shRNAs or the HIV-2ROD Vpx protein, induces the reactivation of HSV-1 in infected primary human fibroblasts as well as in human induced pluripotent stem cell-derived sensory neurons (hiPSDN). We discovered that the viral protein ICP0 induces MORC2 degradation via the proteasome machinery. This process is concurrent with ICP0 capability to initiate full HSV-1 reactivation, as well as the significant reactivation of HSV-1 upon MORC2 depletion in hiPSDN. Our data demonstrate the potent antiviral restriction activity of the HUSH/SETDB1/MORC2 complex to a non-integrated human herpesvirus, its close association with PML NBs, and introduces a new target for anti-herpesvirus therapy.

2024-09-24 | GSE263436 | GEO

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