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Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208689 | GEO | 2023/07/06

REPOSITORIES: GEO

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Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [WGBS]

Project description:We inactivated RYBP, YAF2, TET1, TET2, and TET3 in bronchial cells, individually and in combination, and observed widespread DNA methylation by performing whole genome bisulfite sequencing.

2023-07-06 | GSE208688 | GEO

Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [ChIP-seq]

Project description:We assessed the levels of the PRC1 Polycomb mark, RYBP, H2AK119Ub1, and the PRC2 Polycomb mark, H3K27me3, considering the extensive crosstalk between PRC1 and PRC2 activities.

2023-07-06 | GSE208687 | GEO

Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [RNA-seq]

Project description:To investigate the function of RYBP, YAF2, TET1, TET2, TET3 or the cooperative function in the human bronchial cells, we established defective clone cell lines in which each target gene has been knocked out by guide RNA We then performed gene expression profiling analysis from mRNA-seq.

2023-07-06 | GSE208686 | GEO

Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation.

Project description:Hypermethylation of CpG islands (CGI) is a common feature of cancer cells and predominantly affects Polycomb-associated genomic regions. Elucidating the underlying mechanisms leading to DNA hypermethylation in human cancer could help identify chemoprevention strategies. Here, we evaluated the role of Polycomb complexes and 5-methylcytosine (5mC) oxidases in protecting CGIs from DNA methylation and observed that four genes coding for components of Polycomb repressive complex 1 (PRC1) are downregulated in tumors. Inactivation of RYBP, a key activator of variant PRC1 complexes, in combination with all three 5mC oxidases (TET proteins) in nontumorigenic bronchial epithelial cells led to widespread hypermethylation of Polycomb-marked CGIs affecting almost 4,000 target genes, which closely resembled the DNA hypermethylation landscape observed in human squamous cell lung tumors. The RYBP- and TET-deficient cells showed methylation-associated aberrant regulation of cancer-relevant pathways, including defects in the Hippo tumor suppressor network. Notably, the quadruple knockout cells acquired a transformed phenotype, including anchorage-independent growth and formation of squamous cell carcinomas in mice. This work provides a mechanism promoting hypermethylation of CGIs and shows that such hypermethylation can lead to cell transformation. The breakdown of a two-pronged protection mechanism can be a route towards genome-wide hypermethylation of CGIs in tumors.SignificanceDysfunction of the Polycomb component RYBP in combination with loss of 5-methylcytosine oxidases promotes widespread hypermethylation of CpG islands in bronchial cells and induces tumorigenesis, resembling changes seen in human lung tumors.

| S-EPMC10391329 | biostudies-literature

Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation

Project description:Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation

| PRJNA860612 | ENA

Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [WGBS]

Project description:Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [WGBS]

| PRJNA860621 | ENA

Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [RNA-seq]

Project description:Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [RNA-seq]

| PRJNA860609 | ENA

Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [ChIP-seq]

Project description:Dysfunction of 5-methylcytosine oxidases and the Polycomb protein RYBP leads to widespread DNA hypermethylation and cell transformation [ChIP-seq]

| PRJNA860622 | ENA

Polycomb protein RYBP facilitates super-enhancer activity

Project description:Background Polycomb proteins are conventionally known as global repressors in cell fate determination. However, recent observations have shown their involvement in transcriptional activation, the mechanisms of which need to be further revealed. Methods Herein, multiple data from ChIP-seq, RNA-seq and HiChIP before or after RYBP depletion in embryonic stem cell (ESC), epidermal progenitor (EPC) and mesodermal cell (MEC) were analyzed. Results We found that Polycomb protein RYBP occupies at super-enhancer (SE) in ESCs, where core Polycomb group (PcG) components such as RING1B and EZH2 are minimally enriched. Depletion of RYBP results in impaired deposition of H3K27ac, decreased expression of SE-associated genes, and reducing the transcription of enhancer RNA at SE regions (seRNA). Regarding the mechanism of seRNA transcription, the Trithorax group (TrxG) component WDR5 co-localizes with RYBP at SEs, and is required for seRNA expression. RYBP depletion reduces WDR5 deposition at SE regions. In addition, TrxG-associated H3K4me3 tends to be enriched at the SEs with high levels of seRNA transcription, and RYBP deficiency impairs the deposition of H3K4me3 at SEs. Structurally, RYBP is involved in both intra- and inter-SE interactions. Finally, RYBP generally localizes at SEs in EPCs and MECs, dysfunction of RYBP is associated with various cancers and developmental diseases. Conclusion RYBP cooperates with TrxG component to regulate SE activity. Dysfunction of RYBP relates to various diseases. The findings provide new insights into the transcriptionally active function of Polycomb protein in cell fate determination.

2024-11-13 | GSE281406 | GEO

RYBP stimulates PRC1 to shape chromatin-based communication between Polycomb repressive complexes.

Project description:Polycomb group (PcG) proteins function as chromatin-based transcriptional repressors that are essential for normal gene regulation during development. However, how these systems function to achieve transcriptional regulation remains very poorly understood. Here, we discover that the histone H2AK119 E3 ubiquitin ligase activity of Polycomb repressive complex 1 (PRC1) is defined by the composition of its catalytic subunits and is highly regulated by RYBP/YAF2-dependent stimulation. In mouse embryonic stem cells, RYBP plays a central role in shaping H2AK119 mono-ubiquitylation at PcG targets and underpins an activity-based communication between PRC1 and Polycomb repressive complex 2 (PRC2) which is required for normal histone H3 lysine 27 trimethylation (H3K27me3). Without normal histone modification-dependent communication between PRC1 and PRC2, repressive Polycomb chromatin domains can erode, rendering target genes susceptible to inappropriate gene expression signals. This suggests that activity-based communication and histone modification-dependent thresholds create a localized form of epigenetic memory required for normal PcG chromatin domain function in gene regulation.

| S-EPMC5065315 | biostudies-literature

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