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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262482 | GEO | 2024/03/26

REPOSITORIES: GEO

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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

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Assessing the genome-wide occupancy of MORC2

Project description:By comparing HeLa cells expressing V5 epitope-tagged MORC2 constructs, the goal of the experiment was to determine the genome-wide localisation of MORC2 in the presence or absence of the HUSH complex and upon inactivation of the CW domain. The occupancy of V5-MORC2 was also compared to that of endogenous TASOR.

2017-05-29 | GSE95451 | GEO

Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors

Project description:DNA methylation is an important epigenetic modification that is thought to contribute to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements (TEs). In this study we used CRISPR/Cas9 mediated gene editing to disrupt DNMT1, the key maintenance methyltransferase in somatic human cells. Surprisingly, and in contrast to findings in mouse, inactivation of DNMT1 in human neural progenitor cells (hNPCs) resulted in viable proliferating cells that maintained the expression of appropriate marker genes. Removal of DNA methylation in hNPCs resulted in a specific activation of hominid-specific LINE-1 elements (L1s), while other classes of TEs remained silent. We also found that the transcriptionally activated L1s acted as alternative promoters for many protein-coding genes involved in neuronal functions, uncovering an L1-based transcriptional network influencing neuronal protein-coding genes. Our results prove novel mechanistic insight into the role of DNA methylation in somatic human cells.

2019-05-30 | PXD008648 | Pride

The HUSH complex cooperates with TRIM28 to repress young retrotransposons and new genes

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

Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors

Project description:DNA methylation is thought to contribute to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements (TEs). In this study, we used CRISPR/Cas9 technology to delete DNMT1, the key maintenance DNA methyltransferase in human neural progenitor cells (hNPCs). Surprisingly, and in contrast to previous findings in mouse somatic cells, inactivation of DNMT1 in hNPCs resulted in viable proliferating cells despite the global loss of DNA CpG-methylation. DNA demethylation led to specific transcriptional activation and chromatin remodeling of evolutionarily young, hominoid-specific LINE-1 elements (L1s), while older L1s and other classes of TEs remained silent. The activated L1s acted as alternative promoters for many protein-coding genes involved in neuronal functions, revealing a hominoidspecific L1-based transcriptional network controlled by DNA methylation that influences neuronal protein-coding genes. Our results give a novel mechanistic insight into the role of DNA methylation in silencing TEs in somatic human cells, as well as further implicating L1s in human brain development and disease.

2019-05-29 | GSE107580 | GEO

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

Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators

Project description:Transposable elements (TEs) are now recognized not only as parasitic DNA, whose spread in the genome must be controlled by the host, but also as major players in shaping genome evolution and providing genetic substrates for evolving new regulatory functions. Long INterspersed Element-1 (LINE-1 or L1), the only currently autonomous mobile transposon in humans, occupies 17% of the genome and continues to generate inter- and intra-individual genetic variation, in some cases resulting in disease. Nonetheless, our knowledge of how L1 activity is controlled and what function L1s play in host gene regulation remains fragmentary. Here, we use CRISPR/Cas9 screening strategies in two distinct human cell lines to provide the first genome-wide survey of genes involved in L1 retrotransposition control. Through this approach we identified functionally diverse genes that either promote or restrict L1 retrotransposition. These factors control the L1 life cycle at transcriptional or post-transcriptional levels, and in a manner which in some, but not in other cases depends on the endogenous L1 sequence, underscoring the complexity of L1 regulation. We further investigated L1 restriction by three candidate regulators, MORC2 and HUSH (human silencing hub) complex subunits TASOR and MPP8. HUSH/MORC2 selectively bind evolutionarily young, full-length L1s immersed within transcriptionally permissive euchromatic environment, and promote H3K9me3 deposition for transcriptional silencing. Interestingly, these silencing events often occur within introns of transcriptionally active host genes, and lead to down-regulation of host gene expression in a HUSH/MORC2-dependent manner. Together, our data provide a rich resource for studies of L1 retrotransposition, elucidate a novel L1 restriction pathway, and illustrate how epigenetic silencing of TEs can influence host gene expression programs.

2017-12-06 | GSE95374 | GEO

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