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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107580 | GEO | 2019/05/29

REPOSITORIES: GEO

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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

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

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.

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

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LSH facilitates DNA methylation primarily by promoting UHRF1 DNA accessibility and DNA methylation by DNMT1

Project description:Accumulative studies indicate that DNA maintenance methylation by DNMT1 is initiated by binding of UHRF1 to replication fork. However, how UHRF1 gains access to chromatin in S phase is poorly understood. Here we report that LSH, a SNF2 family chromatin remodeler, facilitates DNA methylation in somatic cells primarily by promoting DNA methylation by DNMT1. We show that knockout of LSH in various somatic cells resulted in substantial reduction of DNA methylation, whereas knockout of DNMT3A and DNMT3B only moderately reduced the level of DNA methylation. Consistent with a role in maintenance methylation, genome-wide analysis of DNA methylation revealed a widespread reduction of DNA methylation in all genomic elements in LSH null cells. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association, UHRF1-catalyzed H3 ubiquitination, and subsequent DNMT1 recruitment to replication fork. Notably, UHRF1 also enhances LSH association with replication fork. Thus, our study identifies LSH as an essential factor for maintenance methylation and provides novel insight into how LSH facilitates maintenance methylation.

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DNMT1 IP-MS alalysis to identify ubiquitin-dependent interacting partners

Project description:Stable inheritance of DNA methylation is critical for maintaining the differentiated phenotypes in multicellular organisms. However, the molecular basis ensuring high fidelity of maintenance DNA methylation is largely unknown. Here, we demonstrate that two distinct modes of DNMT1 recruitment, one is DNA replication-coupled and the other is uncoupled mechanism, regulate the stable inheritance of DNA methylation. PCNA-associated factor 15 (PAF15) represents a primary target of UHRF1 and undergoes dual mono-ubiquitylation (PAF15Ub2) on chromatin. PAF15Ub2 specifically interacts with DNMT1 and controls the recruitment of DNMT1 in a DNA replication-coupled manner. Thus, loss of PAF15Ub2 results in impaired DNA methylation at sites replicating during early S phase. In contrast, outside of S phase or when PAF15 ubiquitylation is perturbed, UHRF1 ubiquitylates histone H3 to promote DNMT1 recruitment. Together, we identify replication-coupled and uncoupled mechanisms of maintenance DNA methylation, both of which collaboratively ensure the stable DNA methylation.

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DNMT1 Maintains Progenitor Function in Self-Renewing Somatic Tissue

2009-11-12 | GSE18590 | GEO

DNMT1 Maintains Progenitor Function in Self-Renewing Somatic Tissue

Project description:Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation. DNA methylation provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1) maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance, a clear role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is uncharacterized. Here we show that DNMT1 is essential for supporting epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. These effects correlated with DNA methylation as genome-wide analysis revealed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Gene expression analysis: To establish a differentiation signature for primary human keratinocytes, total RNA was isolated in biologic duplicate from cells cultured in growth conditions and high calcium differentiation conditions and hybridized to Affymetrix HG-U133 2.0 Plus arrays. This gene signature was also compared to DNMT1 deficient cells cultured in growth conditions. Methylated DNA profiling: To globally characterize DNA methylation in primary human keratinocytes, genomic DNA was immunoprecipitated using a 5-methylcytidine antibody, amplified, and hybridized to NimbleGen HG18 promoter tiling arrays. Profiling was done using DNA isolated in growth conditions as well as differentiation conditions.

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