Similar Datasets
Project description:The fetal (HbF)-to-adult (HbA) hemoglobin switch is a paradigm for developmental gene expression control with relevance to sickle cell disease and beta-thalassemia. Polycomb repressive complex (PRC) proteins regulate this switch, and an inhibitor of the EED subunit of PRC2 entered clinical trials for fetal hemoglobin activation. Yet, how PcG complexes function in this process, their target genes and relevant subunit composition are unknown. Here, we identified the PRC1 subunit BMI1 as a novel HbF repressor. We uncovered LIN28B, IGF2BP1, and IGF2BP3 as direct BMI1 targets and demonstrate that they account for the BMI1 effects. BMI1 functions as part of the canonical PRC1 (cPRC1) subcomplex as revealed by the physical and functional dissection of BMI1 protein partners. Lastly, we demonstrate that BMI1/cPRC1 acts in concert with the PRC2 to repress HbF through the same target genes. Our study illuminates how PRC silences HbF, highlighting an epigenetic mechanism involved in hemoglobin switching.
2023-03-01 | GSE218232 | GEO
Project description:The fetal (HbF)-to-adult (HbA) hemoglobin switch is a paradigm for developmental gene expression control with relevance to sickle cell disease and beta-thalassemia. Polycomb repressive complex (PRC) proteins regulate this switch, and an inhibitor of the EED subunit of PRC2 entered clinical trials for fetal hemoglobin activation. Yet, how PcG complexes function in this process, their target genes and relevant subunit composition are unknown. Here, we identified the PRC1 subunit BMI1 as a novel HbF repressor. We uncovered LIN28B, IGF2BP1, and IGF2BP3 as direct BMI1 targets and demonstrate that they account for the BMI1 effects. BMI1 functions as part of the canonical PRC1 (cPRC1) subcomplex as revealed by the physical and functional dissection of BMI1 protein partners. Lastly, we demonstrate that BMI1/cPRC1 acts in concert with the PRC2 to repress HbF through the same target genes. Our study illuminates how PRC silences HbF, highlighting an epigenetic mechanism involved in hemoglobin switching.
2023-03-01 | GSE218231 | GEO
Project description:Enhancer of Zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2) that regulates many essential biological processes, including embryogenesis and many developmental events. The oncogenic role of EZH2 has recently been implicated in several cancer types. In this study, we first confirmed that the over-expression of EZH2 is a frequent event in oral tongue squamous cell carcinoma (OTSCC). We further demonstrated that EZH2 over-expression is correlated with advanced stages of the disease and is associated with lymph node metastasis. Statistical analysis revealed that EZH2 over-expression was correlated with reduced overall survival. Furthermore, over-expression of EZH2 was correlated with reduced expression of tumor suppressor gene E-cadherin. These observations were confirmed in vitro, in which knockdown of EZH2-induced E-cadherin expression and reduced cell migration and invasion. In contrast, ectopic transfection of EZH2 led to reduced E-cadherin expression and enhanced cell migration and invasion. Furthermore, EZH2 may act on cell migration in part by suppressing the E-cadherin expression. Taken together, these data suggest that EZH2 plays major roles in the progression of OTSCC, and may serve as a biomarker or therapeutic target for patients at risk of metastasis.
| S-EPMC3400713 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-04-19 | GSE202872 | GEO
Project description:Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.
| S-EPMC2690514 | biostudies-literature
Project description:Lethal(3) malignant brain tumour like 2 (L3MBTL2) is an integral component of the polycomb repressive complex 1.6 (PRC1.6) and has been implicated in transcriptional repression and chromatin compaction. Here, we show that L3MBTL2 is modified by SUMO2/3 at lysine residues 675 and 700 close to the C-terminus. SUMOylation of L3MBTL2 neither affected its repressive activity in reporter gene assays nor it's binding to histone tails in vitro. In order to analyse whether SUMOylation affects binding of L3MBTL2 to chromatin, we performed ChIP-Seq analysis with chromatin of wild-type HEK293 cells and with chromatin of HEK293 cells stably expressing either FLAG-tagged SUMOylation-competent or SUMOylation-defective L3MBTL2. Wild-type FLAG-L3MBTL2 and the SUMOylation-defective FLAG-L3MBTL2 K675/700R mutant essentially occupied the same sites as endogenous L3MBTL2 suggesting that SUMOylation of L3MBTL2 does not affect chromatin binding. However, a subset of L3MBTL2-target genes, particularly those with low L3MBTL2 occupancy including pro-inflammatory genes, was de-repressed in cells expressing the FLAG-L3MBTL2 K675/700R mutant. Finally, we provide evidence that SUMOylation of L3MBTL2 facilitates repression of these PRC1.6-target genes by balancing the local H2Aub1 levels established by the ubiquitinating enzyme RING2 and the de-ubiquitinating PR-DUB complex.
| S-EPMC3950706 | biostudies-literature
Project description:The Polycomb group (PcG) proteins have been implicated in epigenetic transcriptional repression in development, stem cell maintenance and in cancer. The chromodomain protein Polycomb (Pc) is a key member of the PcG. Pc binds to the histone mark, trimethylated histone 3 lysine 27 (H3K27me3), to initiate transcriptional repression. How PcG proteins are recruited to target loci is not fully understood. Here we show that the Drosophila SERTA domain protein Taranis (Tara) is involved in transcriptional regulation of Pc target genes. Embryos lacking Tara exhibit a partial homeotic transformation of cuticular the segments, a phenotype associated with the loss of Pc function. Moreover, Drosophila embryos homozygous for a tara hypomorphic allele also misexpress engrailed, a Pc-regulated gene, and this phenotype is associated with the loss of Pc binding to the cis response element in the engrailed enhancer. In relation to that, Pc recruitment is reduced on the salivary gland polytene chromosomes and specifically at the engrailed locus. These results suggest that Tara might be required for positioning Pc to a subset of its target genes.
| S-EPMC5493352 | biostudies-literature
Project description:SPINK1 overexpression defines the second largest subtype of prostate cancer (PCa), however molecular mechanisms underlying its upregulation remains poorly understood. Here, we identified the role of miR-338-5p and miR-421 in post-transcriptional regulation of SPINK1. We established that miR-338-5p/miR-421 mediates several cellular responses against SPINK1-positive cancer by targeting oncogenic long non-coding RNA (lncRNA) MALAT1, inducing cell-cycle arrest, inhibiting epithelial-to-mesenchymal transition (EMT), cancer-stemness and drug resistance. Moreover, ectopic expression of miR-338-5p/miR-421 abrogates SPINK1-mediated oncogenesis, tumor growth and distant metastases in murine model. Importantly, RNA-sequencing expression analysis revealed an inverse correlation between miRNAs and SPINK1 or MALAT1 in PCa patients’ specimens. Further, we demonstrate Polycomb group protein EZH2-mediated epigenetic silencing of miR-338-5p/miR-421 in SPINK1-positive subtype. Thus, restoring miR-338-5p/miR-421 expression using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis by targeting multiple oncogenic pathways and eliciting anti-cancer pleiotropic effects. Taken together, the present study unravels the molecular mechanism underlying SPINK1 overexpression and suggests miR-338-5p and miR-421 replacement therapy for the treatment of SPINK1-positive malignancies.
2018-12-30 | GSE108558 | GEO
Project description:Antagonistic functions of Polycomb and Trithorax proteins are essential for proper development of all metazoans. While the Polycomb proteins maintain the repressed state of many key developmental genes, the Trithorax proteins ensure that these genes stay active in cells where they have to be expressed. Ash1 is the Trithorax protein that was proposed to counteract Polycomb repression by methylating lysine 36 of histone H3. However, it was recently shown that genetic replacement of Drosophila histone H3 with the variant that carried Arginine instead of Lysine at position 36 did not impair the ability of Ash1 to counteract Polycomb repression. This argues that Ash1 counteracts Polycomb repression by methylating yet unknown substrate(s) and that it is time to look beyond Ash1 methyltransferase SET domain, at other evolutionary conserved parts of the protein that received little attention. Here we used Drosophila genetics to demonstrate that Ash1 requires each of the BAH, PHD and SET domains to counteract Polycomb repression, while AT hooks are dispensable. Our findings argue that, in vivo, Ash1 acts as a multimer. Thereby it can combine the input of the SET domain and PHD-BAH cassette residing in different peptides. Finally, using new loss of function alleles, we show that zygotic Ash1 is required to prevent erroneous repression of homeotic genes of the bithorax complex in the embryo.
| S-EPMC6829142 | biostudies-other
Project description:Polycomb group (PcG) complexes regulate cellular identity through epigenetic programming of chromatin. Here, we show that SSX2, a germline-specific protein ectopically expressed in melanoma and other types of human cancers, is a chromatin-associated protein that antagonizes BMI1 and EZH2 PcG body formation and derepresses PcG target genes. SSX2 further negatively regulates the level of the PcG-associated histone mark H3K27me3 in melanoma cells, and there is a clear inverse correlation between SSX2/3 expression and H3K27me3 in spermatogenesis. However, SSX2 does not affect the overall composition and stability of PcG complexes, and there is no direct concordance between SSX2 and BMI1/H3K27me3 presence at regulated genes. This suggests that SSX2 antagonizes PcG function through an indirect mechanism, such as modulation of chromatin structure. SSX2 binds double-stranded DNA in a sequence non-specific manner in agreement with the observed widespread association with chromatin. Our results implicate SSX2 in regulation of chromatin structure and function.
| S-EPMC4191419 | biostudies-literature