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Epigenetic profiling of EMT in pancreatic cancer cells (ChIP-seq)

ABSTRACT: Epithelial plasticity – reversible modulation of a cell’s epithelial and mesenchymal features – is associated with cancer metastasis and chemoresistance. This process is classically driven by a small cohort of transcription factors, several of which have been reported to functionally interact with epigenetic modifiers at the promoters of key epithelial and mesenchymal genes. However, the extent to which epigenetic changes underlie epithelial plasticity at the genomic level remains largely unknown. Here we show that genome-wide regulation of a single histone mark, H3K36me2, is critical for establishing stable epithelial-mesenchymal states in various genetic, chemical, and cellular contexts. Through targeted CRISPR-Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-mesenchymal identity, tumor differentiation, and metastasis. Using genetic approaches to inhibit H3K36me2, we found that modulation of the mark itself is a conserved mechanism underlying the mesenchymal state. Although H3K36me2 is distributed broadly throughout the genome, it is associated with altered enhancer activity affecting a relatively small number of genes, including those associated with master epithelial-mesenchymal regulatory factors. Our results thus outline an epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE137521 | GEO | 2020/03/13

REPOSITORIES: GEO

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Epigenetic profiling of EMT in pancreatic cancer cells (ATAC-seq)

Project description:Epithelial plasticity – reversible modulation of a cell’s epithelial and mesenchymal features – is associated with cancer metastasis and chemoresistance. This process is classically driven by a small cohort of transcription factors, several of which have been reported to functionally interact with epigenetic modifiers at the promoters of key epithelial and mesenchymal genes. However, the extent to which epigenetic changes underlie epithelial plasticity at the genomic level remains largely unknown. Here we show that genome-wide regulation of a single histone mark, H3K36me2, is critical for establishing stable epithelial-mesenchymal states in various genetic, chemical, and cellular contexts. Through targeted CRISPR-Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-mesenchymal identity, tumor differentiation, and metastasis. Using genetic approaches to inhibit H3K36me2, we found that modulation of the mark itself is a conserved mechanism underlying the mesenchymal state. Although H3K36me2 is distributed broadly throughout the genome, it is associated with altered enhancer activity affecting a relatively small number of genes, including those associated with master epithelial-mesenchymal regulatory factors. Our results thus outline an epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity in cancer.

2020-03-13 | GSE137520 | GEO

Epigenetic profiling of EMT in pancreatic cancer cells (RNA-seq)

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Selvaggio2020 - Microenvironment control of hybrid Epithelial-Mesenchymal phenotypes

Project description:Epithelial to Mesenchymal Transition (EMT) has been associated with cancer cell heterogeneity, plasticity and metastasis. It has been the subject of several modeling effort. This logical model of the EMT cellular network aims to assess microenvironmental signals controlling cancer-associated phenotypes amid the EMT continuum. Its outcomes relate to the qualitative degrees of cell adhesions by adherent junctions and focal adhesions, two features affected during EMT. Model attractors recover epithelial, mesenchymal and hybrid phenotypes, and simulations show that hybrid phenotypes may arise through independent molecular paths, involving stringent extrinsic signals. Of particular interest, model predictions and their experimental validations indicated that: 1) ECM stiffening is a prerequisite for cells overactivating FAK-SRC to upregulate SNAIL1 and acquire a mesenchymal phenotype, and 2) FAK-SRC inhibition of cell-cell contacts through the Receptor Protein Tyrosine Phosphates kappa leads to the acquisition of a full mesenchymal rather than a hybrid phenotype.

2020-06-30 | MODEL2004040001 | BioModels

A critical role of histone deacetylases, Mbd3/NuRD and Tet2 in epithelial-mesenchymal cell plasticity and in tumor invasion and metastasis

Project description:We have generated and employed reversible and irreversible EMT models of murine breast cancer cells to identify the key players establishing cell state transitions during a reversible and an irreversible EMT. We demonstrate that the Mbd3/NuRD complex, involving histone deacetylases (HDACs) and Tet2 hydroxylase, acts as an epigenetic block in epithelial-mesenchymal plasticity. These epigenetic modifiers keep breast cancer cells in a stable mesenchymal state, and their pharmacological inhibition or genetic ablation leads to a mesenchymal-epithelial transition (MET) and represses primary tumor growth and metastasis formation of highly aggressive, mesenchymal breast cancer cells.

2020-04-10 | GSE100553 | GEO

KMT9 writes the histone mark H4K12me1 and controls metabolism and proliferation of castration-resistant prostate cancer cells

Project description:Posttranslational modifications of histones such as methylation regulate chromatin structure and gene expression. Methylation of histone lysine residues is generally performed by SET domain methyltransferases. Here, we identify the heterodimeric C21orf127/TRMT112 complex as a specific histone methyltransferase. Assembly of the seven-b-strand protein C21orf127 (also named Hemk2, N6amt1 or PrmC) with TRMT112 is essential to form an active enzyme, hereafter named KMT9 that writes the histone mark H4K12me1 in vitro and in vivo. The H4K12me1 mark is enriched at promoters of KMT9 target genes and co-localises with the active histone mark H4K12ac. By controlling expression of genes involved in energy metabolism, KMT9 regulates oxidative phosphorylation in androgen receptor-dependent and -independent prostate tumour cells. Importantly, KMT9 depletion severely affects proliferation of castration and enzalutamide-resistant prostate cancer cells and xenograft tumours. Together, our data link the writing of the H4K12me1 histone mark by KMT9 with KMT9-dependent gene expression, which in consequence regulates energy metabolism and proliferation. KMT9 executes these functions independently of androgen receptor and androgen signalling thus, providing a promising paradigm for the treatment of castration resistant prostate cancer.

2019-03-11 | PXD008965 | Pride

ASH1L links histone H3 lysine 36 di-methylation to leukemia

Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention. Investigation of multiple transcription factors and histone modification marks in MV4-11 human leukemia cells.

2016-07-01 | E-GEOD-73528 | biostudies-arrayexpress

Expression data from SUM149 inflammatory breast cancer cells cultured in monolayer or Matrigel

Project description:Inflammatory breast cancer (IBC) is a rare type of breast cancer but accounts for up to 10% of breast cancer-related deaths. Plasticity between epithelial and mesenchymal feature is reported to be crucial in metastasis of IBC. Using Matigel culture, we induced epithelial to mesenchymal transition (EMT) in epithelial-like SUM149 IBC cells and identified overexpressed genes in this EMT process.

2018-04-01 | GSE109396 | GEO

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [ChIP]

Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. ChIP sequencing of H3K36me2 ChIP DNA from KMS11 and TKO2 cells using Illumina Solexa Genome Analyzer II single end sequencing protocol. The experiment contains two biological replicates of H3K36me2 ChIP DNA and input materials from KMS11 and TKO2 cells.

2011-11-29 | E-GEOD-29146 | biostudies-arrayexpress

Genome-wide analysis of H3.3, H3K36me2, H3K36me3 and ZMYND11 accumulation in WT MEFs and NSD2 KO MEFs.

Project description:We found that the incorporation of histone H3 variant H3.3 was impaired and the accumulation of ZMYND11, which specifically binds to H3.3K36me3, was decreased in NSD2 KO MEFs. About H3K36me2, the average gene body profiles of H3K36me2 showed preferential enrichment of H3K36me2 at the promoter and first half of the genic regions. We examined H3K36me2 mark in super enhancer regions using the ROSE super enhancer prediction program and identified of the 519 super enhancer islands of H3K36me2 in WT MEFs the H3K36me2 signals were decreased in NSD2 KO MEFs

2019-12-31 | GSE97277 | GEO

Gene expression profiles of forced miR-200 expression in 344SQ lung adenocarcinoma cells with high metastatic potential

Project description:Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here we addressed this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. A feature of metastasis-prone tumor cells that distinguished them from metastasis-incompetent tumor cells was plasticity in response to changes in their microenvironment. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in 3-dimensional culture that underwent epithelial-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This plasticity was entirely dependent upon the microRNA-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that microenvironmental cues direct tumor metastasis by regulating miR-200 expression.

2009-11-10 | GSE15741 | GEO

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