Pasini, D. et al. Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-repressive complex 2. Genes Dev. 22, 1345-1355
Polycomb group (PcG) proteins regulate important cellular processes such as embryogenesis, cell proliferation, and stem cell self-renewal through the transcriptional repression of genes determining cell fate decisions. The Polycomb-Repressive Complex 2 (PRC2) is highly conserved during evolution, and its intrinsic histone H3 Lys 27 (K27) trimethylation (me3) activity is essential for PcG-mediated transcriptional repression. Here, we show a functional interplay between the PRC2 complex and the H3K4me3 demethylase Rbp2 (Jarid1a) in mouse embryonic stem (ES) cells. By genome-wide location analysis we found that Rbp2 is associated with a large number of PcG target genes in mouse ES cells. We show that the PRC2 complex recruits Rbp2 to its target genes, and that this interaction is required for PRC2-mediated repressive activity during ES cell differentiation. Taken together, these results demonstrate an elegant mechanism for repression of developmental genes by the coordinated regulation of epigenetic marks involved in repression and activation of transcription.
[Show abstract] [Hide abstract] ABSTRACT: Chromatin regulators play an important role in the development of human diseases. In this study, we focused on Plant Homeo Domain Finger protein 8 (PHF8), a chromatin regulator that has attracted special concern recently. PHF8 is a histone lysine demethylase ubiquitously expressed in nuclei. Mutations of PHF8 are associated with X-linked mental retardation. It usually functions as a transcriptional co-activator by associating with H3K4me3 and RNA polymerase II. We found that PHF8 may associate with another regulator, REST/NRSF, predominately at promoter regions via studying several published PHF8 chromatin immunoprecipitation-sequencing (ChIP-Seq) datasets. Our analysis suggested that PHF8 not only activates but may also repress gene expression.0Comments 1Citation
- "PHF8 is a JmjC domain-containing protein and erases repressive histone marks including H4K20me1 and H3K9me1/24567. It binds to H3K4me3, an active histone mark usually located at transcription start sites (TSSs)89, through its plant homeo-domain, and is thus recruited and enriched in gene promoters. Chromatin immunoprecipitation-sequencing (ChIP-seq) data from immortalized human HeLa cells show that about 72% of PHF8 binding sites are at promoters5. "
[Show abstract] [Hide abstract] ABSTRACT: The molecular mechanisms responsible for angiogenesis and abnormal expression of angiogenic factors in gastric cancer, including vascular endothelial growth factor (VEGF), remain unclear. The histone demethylase retinoblastoma binding protein 2 (RBP2) is involved in gastric tumorgenesis by inhibiting the expression of cyclin-dependent kinase inhibitors (CDKIs). The expression of RBP2, VEGF, CD31, CD34 and Ki67 was assessed in 30 human gastric cancer samples and normal control samples. We used quantitative RT-PCR, western blot analysis, ELISA, tube-formation assay and colony-formation assay to characterize the change in VEGF expression and associated biological activities induced by RBP2 silencing or overexpression. Luciferase assay and ChIP were used to explore the direct regulation of RBP2 on the promoter activity of VEGF. Nude mice and RBP2-targeted mutant mice were used to detect the role of RBP2 in VEGF expression and angiogenesis in vivo. RBP2 and VEGF were both overexpressed in human gastric cancer tissue, with greater microvessel density (MVD) and cell proliferation as compared with normal tissue. In gastric epithelial cell lines, RBP2 overexpression significantly promoted the expression of VEGF and the growth and angiogenesis of the cells, while RBP2 knockdown had the reverse effect. RBP2 directly bound to the promoter of VEGF to regulate its expression by histone H3K4 demethylation. The subcutis of nude mice transfected with BGC-823 cells with RBP2 knockdown showed reduced VEGF expression and MVD, with reduced carcinogenesis and cell proliferation. In addition, the gastric epithelia of RBP2 mutant mice with increased H3K4 trimethylation showed reduced VEGF expression and MVD. The promotion of gastric tumorigenesis by RBP2 was significantly associated with transactivation of VEGF expression and elevated angiogenesis. Overexpression of RBP2 and activation of VEGF might play important roles in human gastric cancer development and progression.0Comments 4Citations
- "In nude mice, tumors from transfected gastric cancer cells stably expressing RBP2 shRNA were smaller, with lower VEGF expression, and less MVD and cell proliferation than control cells. Recent genome-wide analyses of mouse embryonic stem cells and human leukemic cell lines revealed hundreds of RBP2 target genes and many of them implicated in development, proliferation and differentiation controls [32,38,39]. RBP2 was identified as a key molecule in drug tolerance of cancer cells and maintaining cancer stem cells [40,41]. "
[Show abstract] [Hide abstract] ABSTRACT: During embryonic development a large number of widely differing and specialized cell types with identical genomes are generated from a single totipotent zygote. Tissue specific transcription factors cooperate with epigenetic modifiers to establish cellular identity in differentiated cells and epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns, a phenomenon referred to as epigenetic memory. This is accomplished via the stable maintenance of various epigenetic marks through successive rounds of cell division. Preservation of DNA methylation patterns is a well-established mechanism of epigenetic memory, but more recently it has become clear that many other epigenetic modifications can also be maintained following DNA replication and cell division. In this review, we present an overview of the current knowledge regarding the role of histone lysine methylation in the establishment and maintenance of stable epigenetic states.0Comments 5Citations
- "The H3K4me3 demethylase, Jarid1a, and the H3K27me3 demethylases, Jmjd3 and UTX, counteract the TrxG and PcG complexes, thereby helping to resolve the bivalent domains during ES cell differentiation. Jarid1a is recruited by the PRC2 complex to PcG target genes in ES cells to repress their expression (Pasini et al., 2008). During ES cell differentiation Jarid1a dissociates from the classical PcG target genes, the Hox genes, resulting in an increased H3K4me3 levels and gene activation (Christensen et al., 2007). "