Histone variant H3.3 promotes experimental metastasis in alveolar rhabdomyosarcoma [RNA-Seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE204855 | GEO | 2022/12/15
REPOSITORIES: GEO
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Project description:In this study, we show that histone variant H3.3 is overexpressed in ARMS patient-derived cell lines and patient tumour specimens. Functionally, knockdown of H3F3A significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation in vitro. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Through RNA-sequencing and ChIP-sequencing analyses, we identified Melanoma Cell Adhesion Molecule (MCAM/CD146) as a direct downstream target of H3.3. Therefore, this study identifies a novel H3.3- MCAM axis involved in ARMS metastatic phenotypes, and supports the development of MCAM as a therapeutic target for this disease.
2022-12-15 | GSE203614 | GEO
Project description:Study to investigate the role of histone residues H3K4 and H3K36 for gene expression, histone localization and neuronal lineage specification by mutation of K4 and K36 in H3.3 to alanine. Histone variant H3.3 differs from the canonical H3.1/H3.2 by only 4 to 5 amino acids, which are necessary for nucleosome assembly independent of DNA replication, and is encoded by two gene copies. Complete loss of the two H3.3 genes (H3f3a and H3f3b) leads to embryonic lethality while single gene knockout yields viable mice. We used CRISPR-Cas9 to delete H3f3a and introduce homozygous point-mutations into H3f3b, thus ensuring that the entire pool of H3.3 protein carries the mutation of interest. We differentiated H3.3ctrl (H3f3a knock-out; H3f3b wild type), H3.3K4A mutant (H3f3a knock-out; H3f3b K4A) and H3.3K36A mutant (H3f3a knock-out; H3f3b K36A) ESCs into glutamatergic neurons. To assess the effect of the K4A mutation on Pol II activity, nascent RNA levels were mesaured by PRO-seq.
2020-01-28 | E-MTAB-8617 | biostudies-arrayexpress
Project description:Study to investigate the role of histone residues H3K4 and H3K36 for gene expression, histone localization and neuronal lineage specification by mutation of K4 and K36 in H3.3 to alanine. Histone variant H3.3 differs from the canonical H3.1/H3.2 by only 4 to 5 amino acids, which are necessary for nucleosome assembly independent of DNA replication, and is encoded by two gene copies. Complete loss of the two H3.3 genes (H3f3a and H3f3b) leads to embryonic lethality while single gene knockout yields viable mice. We used CRISPR-Cas9 to delete H3f3a and introduce homozygous point-mutations into H3f3b, thus ensuring that the entire pool of H3.3 protein carries the mutation of interest. We differentiated H3.3ctrl (H3f3a knock-out; H3f3b wild type), H3.3K4A mutant (H3f3a knock-out; H3f3b K4A) and H3.3K36A mutant (H3f3a knock-out; H3f3b K36A) ESCs into glutamatergic neurons. Gene expression profiles were measured by mRNA-Sequencing in undifferentiated ESCs (D0), neurodevelopment (D8) and differentiated neurons (D12) to assess the impact of the mutation on gene expression and development.
2020-01-28 | E-MTAB-6821 | biostudies-arrayexpress
Project description:Study to investigate the role of histone residues H3K4 and H3K36 for gene expression, histone localization and neuronal lineage specification by mutation of K4 and K36 in H3.3 to alanine. Histone variant H3.3 differs from the canonical H3.1/H3.2 by only 4 to 5 amino acids, which are necessary for nucleosome assembly independent of DNA replication, and is encoded by two gene copies. Complete loss of the two H3.3 genes (H3f3a and H3f3b) leads to embryonic lethality while single gene knockout yields viable mice. We used CRISPR-Cas9 to delete H3f3a and introduce homozygous point-mutations into H3f3b, thus ensuring that the entire pool of H3.3 protein carries the mutation of interest. We differentiated H3.3ctrl (H3f3a knock-out; H3f3b wild type), H3.3K4A mutant (H3f3a knock-out; H3f3b K4A) and H3.3K36A mutant (H3f3a knock-out; H3f3b K36A) ESCs into glutamatergic neurons. Genomic localization of H3.3 protein was determined by ChIP-Sequencing in ESCs (D0). Distribution patterns of RNA Polymerase II Phosphorylated on Serine 5 (RNA Pol II Ser5P), of histone modification H3K27me3 and chromatin remodeler components Brg1/Smarca4 (Swi/Snf) and Chd4 (NuRD) were measured by ChIP-Sequencing in ESCs (D0) to assess the impact of the H3.3K4A mutation on the epigenetic landscape. Distribution patterns of H3.3 were assessed by ChIP-Sequencing in HEK293T cells after depletion of Brg1/Smarca4 (Swi/Snf) and Chd4 (NuRD).
2020-01-28 | E-MTAB-8614 | biostudies-arrayexpress
Project description:Study to investigate the role of histone residues H3K4 and H3K36 for gene expression, histone localization and neuronal lineage specification by mutation of K4 and K36 in H3.3 to alanine. Histone variant H3.3 differs from the canonical H3.1/H3.2 by only 4 to 5 amino acids, which are necessary for nucleosome assembly independent of DNA replication, and is encoded by two gene copies. Complete loss of the two H3.3 genes (H3f3a and H3f3b) leads to embryonic lethality while single gene knockout yields viable mice. We used CRISPR-Cas9 to delete H3f3a and introduce homozygous point-mutations into H3f3b, thus ensuring that the entire pool of H3.3 protein carries the mutation of interest. We differentiated H3.3ctrl (H3f3a knock-out; H3f3b wild type), H3.3K4A mutant (H3f3a knock-out; H3f3b K4A) and H3.3K36A mutant (H3f3a knock-out; H3f3b K36A) ESCs into glutamatergic neurons. Genomic localization of H3.3 protein was determined by ChIP-Sequencing in ESCs (D0). Histone modifications patterns of H3K4me1, H3K4me3 and H3K27ac were measured by ChIP-Sequencing in ESCs (D0) to assess the impact of the H3.3K4A mutation on the epigenetic landscape. Levels of H3K36me3 were measured by ChIP-Sequencing in WT and H3.3K36A mutant ESCs (D0), NPCs (D8) and neurons (D12) to assess the impact of the H3.3K36A mutation on H3K36me3 levels in development.
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Project description:Gene expression profile of CD4+ tumor infiltrating lymphocytes from three renal carcinoma patients depending on the expression of Melanoma Cell Adhesion Molecule (MCAM, CD146).
2016-11-10 | E-MTAB-3078 | biostudies-arrayexpress
Project description:Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma, wherein the malignant tumors arise from the myoblast like cells due to the perturbations in growth and differentiation. Alveolar rhabdomyosarcoma (ARMS) is one of the two major histological subtypes which exhibits high metastatic potential and tumor recurrence culminating in poor prognosis. In the recent past, understanding the epigenetic modifications in these tumors with less genetic alterations has shed light on the process of tumor pathogenesis and development of potential epi-drugs for the effective treatment strategies. Epigenetic regulator, Euchromatin histone lysine methyltransferase 1 (EHMT1)/G9A-like protein (GLP) and its homolog Euchromatin histone lysine methyltransferase 1 (EHMT2)/G9A has been shown to promote proliferation and inhibit differentiation in the mouse myoblast cells, independently. Also, previous study from our lab reported the overexpression of EHMT2 and molecular mechanism associated with the oncogenic phenotype in ARMS. However, expression pattern and functional role of EHMT1 in ARMS is unknown. Herein, we investigated the role of EHMT1 in ARMS. Our preliminary data indicated the overexpression of EHMT1 and the associated oncogenic phenotypes in ARMS. Although EHMT1 has shown to be upregulated and correlated with the increased disease severity in several cancers including gastric, esophagus, squamous cell carcinoma, ovarian and breast cancer, the mechanism involved in the EHMT1 mediated tumorigenesis was unclear. Therefore, through our current study we aimed to understand the expression pattern and the mechanism through which EHMT1 regulated cancer phenotypes in ARMS, for this we performed whole transcriptomic analysis in ARMS cell lines upon EHMT1 knockdown for the first time. In addition, we also compared the expression levels of EHMT1 between Human skeletal muscle myoblasts (HSMM) and ARMS patient samples (obtained from St Jude cloud database).
2021-12-08 | GSE179049 | GEO
Project description:Although several somatic single nucleotide variations in histone H3.3 have been investigated as cancer drivers, other types of aberrations have not been well studied. Here, we demonstrate that overexpression of H3F3A, encoding H3.3, is associated with lung cancer progression and promotes lung cancer cell migration by activating metastasis-related genes. H3.3 globally activates gene expression through the occupation of intronic regions in lung cancer cells. Moreover, H3.3 binding regions show characteristics of regulatory DNA elements. We show that H3.3 is deposited at a specific intronic region of GPR87, where it modifies the chromatin status and directly activates GPR87 transcription. The expression levels of H3F3A and GPR87, either alone or in combination, are robust prognostic markers for early stage lung cancer, and may indicate potential for the development of treatments involving GPR87 antagonists. Our results demonstrate that intronic regulation by H3F3A may be a target for the development of novel therapeutic strategies. We performed microarray-based global gene expression analysis of H3F3A-overexpressing and H3F3A knockdown A549 cells.
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Project description:Metastasis is a complex process involving loss of adhesion, migration, invasion and proliferation of cancer cells. Cell adhesion molecules play a pivotal role in this phenomenon by regulating cell-cell and cell-matrix interactions. CD146 (MCAM) is associated with advanced tumor stage in melanoma, prostate and ovarian cancers. For this study, the MDA-MB-231 cell line was used as a prototypic mesenchymal and invasive cell line, spontaneously expressing high levels of CD146. Using whole-genome DNA microarrays, we investigated genes for which expression was modified by CD146 down-regulation, obtained by siRNA or shRNA technology
2008-07-11 | GSE11951 | GEO