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Methylation-mediated retuning on the enhancer-to-silencer activity scale of networked regulatory elements guides driver-gene misregulation

ABSTRACT: Cancers arise when particular disease-driving genes adopt abnormal functions, but sequence analyses of coding and regulatory elements leave many of these abnormalities unexplained. We developed a strategy to explore the activities of silencers and enhancers in cancer tumors. Applying the method to human glioblastomas, we produced a driver-gene wide dataset of regulatory elements. Many genes were associated with multiple silencers and enhancers, which cooperatively controlled their expression. Surprisingly, DNA methylation induces enhancers and silencers to acquire new activity setpoints, ranging between strong transcriptional enhancing to strong silencing. Integration of these effects into mathematical models of gene expression resolved the molecular events underlying cancer-genes misregulation in hitherto unexplained tumors. Gene-malfunctioning events due to epigenetically-retuned enhancers or silencers outnumbered causative coding or regulatory sequence alterations, hence dominated driver-genes mutagenesis. The elucidation of this principal gene-transformation mechanism may open the way for methodological disclosing of the driving forces behind cancers and other diseases

ORGANISM(S): Homo sapiens

PROVIDER: GSE163019 | GEO | 2023/10/18

REPOSITORIES: GEO

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Methylation-mediated retuning on the enhancer-to-silencer activity scale of networked regulatory elements guides driver-gene misregulation

Project description:Cancers arise when particular disease-driving genes adopt abnormal functions, but sequence analyses of coding and regulatory elements leave many of these abnormalities unexplained. We developed a strategy to explore the activities of silencers and enhancers in cancer tumors. Applying the method to human glioblastomas, we produced a driver-gene wide dataset of regulatory elements. Many genes were associated with multiple silencers and enhancers, which cooperatively controlled their expression. Surprisingly, DNA methylation induces enhancers and silencers to acquire new activity setpoints, ranging between strong transcriptional enhancing to strong silencing. Integration of these effects into mathematical models of gene expression resolved the molecular events underlying cancer-genes misregulation in hitherto unexplained tumors. Gene-malfunctioning events due to epigenetically-retuned enhancers or silencers outnumbered causative coding or regulatory sequence alterations, hence dominated driver-genes mutagenesis. The elucidation of this principal gene-transformation mechanism may open the way for methodological disclosing of the driving forces behind cancers and other diseases

2023-10-18 | GSE163020 | GEO

A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression

Project description:Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs), enhancers and silencers. While enhancers have been thoroughly characterized, the properties and mechansisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs, as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a highly-conserved domain we term ZAC and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.

2024-11-13 | PXD048161 | Pride

A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression

2024-11-13 | PXD047987 | Pride

human genome-wide silencers

Project description:Silencers, the yin to enhancers' yang, play a pivotal role in fine-tuning gene expression throughout the genome. However, despite their recognized importance, comprehensive identification of these regulatory elements in the genome is still in its early stages. We developed a method called Ss-STARR-seq to directly determine the activity of silencers in the whole genome. In this study, we applied Ss-STARR-seq to human cell lines K562, LNCaP, and 293T, and identified 134,171, 137,753, and 125,307 silencers on a genome-wide scale, respectively, these silencers function in various cells in a cell-specific manner. Silencers exhibited a substantial enrichment of transcriptional-inhibitory motifs, including REST, and demonstrated overlap with the binding sites of repressor transcription factors within the endogenous environment. Interestingly, H3K27me3 did not reflect silencer activity but facilitated the silencer's inhibitory role on gene expression. Additionally, the silencer did not have any significant histone markers at the genome-wide level. Our findings unveil that aspect-silencers not only transition into enhancers throughout diverse cell lines but also achieve functional conversion with insulators. Regarding to biological effects, knockout experiments underscored the functional redundancy and specificity of silencers in regulating gene expression and cell proliferation. In summary, this study pioneers the elucidation of the genome-wide silencer landscape in human cells, delineates their global regulatory features, and identifies specific silencers influencing cancer cell proliferation.

2024-12-06 | GSE283488 | GEO

Information Content Differentiates Enhancers From Silencers in Mouse Photoreceptors

Project description:Enhancers and silencers often depend on the same transcription factors (TFs) and are imperfectly distinguished from each other by genomic assays of TF binding or chromatin state. To identify sequence features that define enhancers and silencers, we assayed massively parallel reporter libraries of genomic sequences targeted by the photoreceptor TF CRX and found instances of enhancer, silencer, or no activity. Both enhancers and silencers contain more TF motifs than inactive sequences, but enhancers contain motifs from a more diverse collection of TFs. We developed a measure of information content that describes the number and diversity of motifs in a sequence and found that, while both enhancers and silencers depend on CRX motifs, enhancers have higher information content. Our results indicate that enhancers contain motifs for a diverse but degenerate collection of TFs, while silencers depend on a smaller and less diverse collection of TFs.

2021-01-30 | GSE165812 | GEO

A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression [Silencer-seq]

Project description:Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs), enhancers and silencers. While enhancers have been thoroughly characterized, the properties and mechansisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a novel class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs, as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a novel highly-conserved domain ZAC and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.

2024-11-19 | GSE254775 | GEO

A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression [RNA-seq]

Project description:Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs), enhancers and silencers. While enhancers have been thoroughly characterized, the properties and mechansisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a novel class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs, as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a novel highly-conserved domain ZAC and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.

2024-11-19 | GSE254774 | GEO

A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression [repressed STARR-seq]

Project description:Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs), enhancers and silencers. While enhancers have been thoroughly characterized, the properties and mechansisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a novel class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs, as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a novel highly-conserved domain ZAC and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.

2024-11-19 | GSE275153 | GEO

A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression [MNase-seq]

Project description:Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs), enhancers and silencers. While enhancers have been thoroughly characterized, the properties and mechansisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a novel class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs, as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a novel highly-conserved domain ZAC and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.

2024-11-19 | GSE274903 | GEO

A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression [ChIP-seq]

Project description:Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs), enhancers and silencers. While enhancers have been thoroughly characterized, the properties and mechansisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a novel class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs, as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a novel highly-conserved domain ZAC and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.

2024-11-19 | GSE254773 | GEO

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