Genome surveillance through repression of intronless mobile elements by the HUSH complex
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ABSTRACT:
PROVIDER: PRJNA750731 | ENA |
REPOSITORIES: ENA
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Project description:All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 Lys9 trimethylation (H3K9me3). How HUSH recognizes and initiates silencing of these invading genetic elements is unknown. Here, we show that HUSH is able to recognize and transcriptionally repress a broad range of long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence of intron splicing. HUSH binds transcripts from the target locus, prior to and independent of H3K9me3 deposition, and target transcription is essential for both initiation and propagation of HUSH-mediated H3K9me3. Genomic data reveals how HUSH binds and represses a subset of endogenous intronless genes generated through retrotransposition of cellular mRNAs. Therefore, intronless cDNA, a hallmark of reverse transcription, provides a versatile means to distinguish invading retroelements from host genes and allows HUSH to protect the genome from ‘non-self’ DNA, despite no prior exposure to the invading element. Our findings reveal the existence of a genome surveillance system and explain how it provides immediate protection against newly acquired elements while avoiding inappropriate repression of host genes.
2021-09-30 | GSE181113 | GEO
Project description:The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Recent studies revealed that HUSH recruitment is dependent on transcription, but a unifying molecular mechanism by which HUSH identifies its targets as ‘non-self’ DNA and selects them for silencing remains unknown. Harnessing a de novo silencing event in ESCs, we uncover distinct modes of HUSH function – one involves co-transcriptional surveillance in the absence of silencing, while the other is associated with H3K9me3 deposition and repression. We demonstrate that HUSH travels with elongating RNAPII, interacts with the transcriptional termination machinery, and accumulates on chromatin in a manner dependent on the termination factor WDR82. We further show that perturbation of endogenous termination signals triggers the switch from HUSH surveillance to silencing. Together, our results uncover an RNAi-independent, co-transcriptional gene silencing mechanism in mammals that senses aberrant termination to distinguish self from non-self.
2023-05-09 | GSE208749 | GEO
Project description:The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Recent studies revealed that HUSH recruitment is dependent on transcription, but a unifying molecular mechanism by which HUSH identifies its targets as ‘non-self’ DNA and selects them for silencing remains unknown. Harnessing a de novo silencing event in ESCs, we uncover distinct modes of HUSH function – one involves co-transcriptional surveillance in the absence of silencing, while the other is associated with H3K9me3 deposition and repression. We demonstrate that HUSH travels with elongating RNAPII, interacts with the transcriptional termination machinery, and accumulates on chromatin in a manner dependent on the termination factor WDR82. We further show that perturbation of endogenous termination signals triggers the switch from HUSH surveillance to silencing. Together, our results uncover an RNAi-independent, co-transcriptional gene silencing mechanism in mammals that senses aberrant termination to distinguish self from non-self.
2023-05-09 | GSE208748 | GEO
Project description:The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Recent studies revealed that HUSH recruitment is dependent on transcription, but a unifying molecular mechanism by which HUSH identifies its targets as ‘non-self’ DNA and selects them for silencing remains unknown. Harnessing a de novo silencing event in ESCs, we uncover distinct modes of HUSH function – one involves co-transcriptional surveillance in the absence of silencing, while the other is associated with H3K9me3 deposition and repression. We demonstrate that HUSH travels with elongating RNAPII, interacts with the transcriptional termination machinery, and accumulates on chromatin in a manner dependent on the termination factor WDR82. We further show that perturbation of endogenous termination signals triggers the switch from HUSH surveillance to silencing. Together, our results uncover an RNAi-independent, co-transcriptional gene silencing mechanism in mammals that senses aberrant termination to distinguish self from non-self.
2023-05-09 | GSE208752 | GEO
Project description:The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Recent studies revealed that HUSH recruitment is dependent on transcription, but a unifying molecular mechanism by which HUSH identifies its targets as ‘non-self’ DNA and selects them for silencing remains unknown. Harnessing a de novo silencing event in ESCs, we uncover distinct modes of HUSH function – one involves co-transcriptional surveillance in the absence of silencing, while the other is associated with H3K9me3 deposition and repression. We demonstrate that HUSH travels with elongating RNAPII, interacts with the transcriptional termination machinery, and accumulates on chromatin in a manner dependent on the termination factor WDR82. We further show that perturbation of endogenous termination signals triggers the switch from HUSH surveillance to silencing. Together, our results uncover an RNAi-independent, co-transcriptional gene silencing mechanism in mammals that senses aberrant termination to distinguish self from non-self.
2023-05-09 | GSE208751 | GEO
Project description:Retrotransposons encompass half of the human genome and contribute to the formation of heterochromatin, which provides nuclear structure and regulates gene expression. Here, we asked if the human silencing hub (HUSH) complex is necessary to silence retrotransposons and whether it collaborates with TRIM28 and the chromatin remodeler ATRX at specific genomic loci. We show that the HUSH complex contributes to de novo repression and DNA methylation of a SVA retrotransposon reporter. By using naïve vs. primed mouse pluripotent stem cells, we reveal a critical role for the HUSH complex in naïve cells, implicating it in programming epigenetic marks in development. While the HUSH component TASOR binds to endogenous retroviruses (ERVs) and L1s, it is mainly required to repress evolutionarily young L1s. TRIM28, in contrast, is necessary to repress both ERVs and young L1s. Genes co-repressed by TRIM28 and TASOR are evolutionarily young, or exhibit tissue-specific expression, are enriched in young L1s and display evidence for regulation through LTR promoters. Finally, we demonstrate that the HUSH complex is also required to repress L1 elements in human cells. Overall, these data indicate that the HUSH complex and TRIM28 co-repress young retrotransposons and new genes rewired by retrotransposon non-coding DNA.
2018-01-17 | GSE107840 | GEO
Project description:The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We found that depletion of HUSH components in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect was mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs and coincided with upregulated LINE-1 RNAs. This included the human-specific family, L1HS, which produced bidirectional RNAs of around 6Kb, as well as ancient primate-conserved LINE-1s. LTRs nearby ISGs were derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs could abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct could activate interferon signaling. Finally, we found that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through RNA sensing and gene-regulatory roles and are controlled by the HUSH complex.
2020-09-28 | GSE135765 | GEO
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
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 | GSE242143 | GEO
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 | GSE240384 | GEO