Correction: Estrogen induces global reorganization of chromatin structure in human breast cancer cells.
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ABSTRACT:
SUBMITTER: PLOS ONE Staff
PROVIDER: S-EPMC4364813 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Correction: Estrogen induces global reorganization of chromatin structure in human breast cancer cells.
PloS one 20150318 3
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Project description:In the cell nucleus, each chromosome is confined to a chromosome territory. This spatial organization of chromosomes plays a crucial role in gene regulation and genome stability. An additional level of organization has been discovered at the chromosome scale: the spatial segregation into open and closed chromatins to form two genome-wide compartments. Although considerable progress has been made in our knowledge of chromatin organization, a fundamental issue remains the understanding of its dynamics, especially in cancer. To address this issue, we performed genome-wide mapping of chromatin interactions (Hi-C) over the time after estrogen stimulation of breast cancer cells. To biologically interpret these interactions, we integrated with estrogen receptor α (ERα) binding events, gene expression and epigenetic marks. We show that gene-rich chromosomes as well as areas of open and highly transcribed chromatins are rearranged to greater spatial proximity, thus enabling genes to share transcriptional machinery and regulatory elements. At a smaller scale, differentially interacting loci are enriched for cancer proliferation and estrogen-related genes. Moreover, these loci are correlated with higher ERα binding events and gene expression. Taken together these results reveal the role of a hormone--estrogen--on genome organization, and its effect on gene regulation in cancer.
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Project description:In the cell nucleus, each chromosome is confined to a chromosome territory. This spatial organization of chromosomes plays a crucial role in gene regulation and genome stability. Recently an additional level of organization has been discovered at the chromosome scale: the spatial segregation into open and closed chromatin to form two genome-wide compartments. Although considerable progress has been made in our knowledge of chromatin organization, a fundamental issue remains the understanding of its dynamic, especially in cancer. To address this issue, we performed genome-wide mapping of intra- and interchromosomal interactions (Hi-C) over the time after estrogen (E2) stimulation of breast cancer cells. To biologically interpret these interactions, we integrated with estrogen receptor alpha (ER alpha) binding events, gene expression and multiple epigenetic marks. We show that E2 induces a global reorganization of genome. More specifically, gene-rich chromosomes as well as areas of open and highly transcribed chromatins are moved spatially closer, thus enabling genes to share transcriptional machinery and regulatory elements. At a lower scale, differentially interacting loci are enriched for cancer proliferation and E2 related genes. We also observe that these differentially interacting loci are correlated with higher ER alpha binding events and gene expression. 5 time points: before E2 (0h) and after E2 (0.5h, 1h, 4h and 24h). For each time point, there are two lanes per sample and two biological replicate samples. Please note that a processed data file corresponds to the merging of 2 replicates, and that there are 2 lanes per replicates (4 files in total per processed data file). Information about data merging is provided in the title of the sample. For instance : 0h_replicate_1_lane 1 0h_replicate_1_lane 2 0h_replicate_2_lane_1 0h_replicate_2_lane_2 are merged to generate the processed data hic_0h-all-1M.IC.csv.gz. Several bin sizes are provided for the same processed data: hic_0h-all-1M.IC.csv.gz hic_0h-all-2M.IC.csv.gz hic_0h-all-4M.IC.csv.gz hic_0h-all-500k.IC.csv.gz are the same processed data, but with different bin sizes.
2013-10-25 | E-GEOD-51687 | biostudies-arrayexpress
Project description:In the cell nucleus, each chromosome is confined to a chromosome territory. This spatial organization of chromosomes plays a crucial role in gene regulation and genome stability. Recently an additional level of organization has been discovered at the chromosome scale: the spatial segregation into open and closed chromatin to form two genome-wide compartments. Although considerable progress has been made in our knowledge of chromatin organization, a fundamental issue remains the understanding of its dynamic, especially in cancer. To address this issue, we performed genome-wide mapping of intra- and interchromosomal interactions (Hi-C) over the time after estrogen (E2) stimulation of breast cancer cells. To biologically interpret these interactions, we integrated with estrogen receptor alpha (ER alpha) binding events, gene expression and multiple epigenetic marks. We show that E2 induces a global reorganization of genome. More specifically, gene-rich chromosomes as well as areas of open and highly transcribed chromatins are moved spatially closer, thus enabling genes to share transcriptional machinery and regulatory elements. At a lower scale, differentially interacting loci are enriched for cancer proliferation and E2 related genes. We also observe that these differentially interacting loci are correlated with higher ER alpha binding events and gene expression.
2013-10-25 | GSE51687 | GEO
Project description:Vav1, a guanine nucleotide exchange factor (GEF) for Rho family GTPases, is a hematopoietic protein involved in a variety of cellular events. In recent years, aberrant expression of Vav1 has been reported in non-hematopoietic cancers including human breast cancer. It remains to be answered how Vav1 is expressed and what Vav1 does in its non-resident tissues. In this study, we aimed to explore the mechanism for Vav1 expression in breast cancer cells in correlation with estrogen-ER pathway. We not only verified the ectopic expression of Vav1 in human breast cancer cell lines, but also observed that Vav1 expression was induced by 17β-estradiol (E2), a typical estrogen receptor (ER) ligand, in ER-positive cell lines. On the other hand, Tamoxifen, a selective estrogen receptor modulator (SERM), and ICI 182,780, an ER antagonist, suppressed the expression of Vav1. The estrogen receptor modulating Vav1 expression was identified to be α form, not β. Furthermore, treatment of E2 increased the transcription of vav1 gene by enhancing the promoter activity, though there was no recognizable estrogen response element (ERE). Nevertheless, two regions at the vav1 gene promoter were defined to be responsible for E2-induced activation of vav1 promoter. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) analyses suggested that ERα might access to the vav1 promoter via interacting with transcription factors, c-Myb and ELF-1. Consequently, the enhanced expression of Vav1 led to the elevation of Cyclin D1 and the progression of cell cycle. The present study implies that estrogen-ER modulates the transcription and expression of Vav1, which may contribute to the proliferation of cancerous cells.
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Project description:Classical dendritic cells (cDCs) are essential for immune responses and differentiate from hematopoietic stem cells via intermediate progenitors, such as monocyte-DC progenitors (MDPs) and common DC progenitors (CDPs). Upon infection, cDCs are activated and rapidly express host defense-related genes, such as those encoding cytokines and chemokines. Chromatin structures, including nuclear compartments and topologically associating domains (TADs), have been implicated in gene regulation. However, the extent and dynamics of their reorganization during cDC development and activation remain unknown. In this study, we comprehensively determined higher-order chromatin structures by Hi-C in DC progenitors and cDC subpopulations. During cDC differentiation, chromatin activation was initially induced at the MDP stage. Subsequently, a shift from inactive to active nuclear compartments occurred at the cDC gene loci in CDPs, which was followed by increased intra-TAD interactions and loop formation. Mechanistically, the transcription factor IRF8, indispensable for cDC differentiation, mediated chromatin activation and changes into the active compartments in DC progenitors, thereby possibly leading to cDC-specific gene induction. Using an infection model, we found that the chromatin structures of host defense-related gene loci were preestablished in unstimulated cDCs, indicating that the formation of higher-order chromatin structures prior to infection may contribute to the rapid responses to pathogens. Overall, these results suggest that chromatin structure reorganization is closely related to the establishment of cDC-specific gene expression and immune functions. This study advances the fundamental understanding of chromatin reorganization in cDC differentiation and activation.
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Project description:Background: Doxorubicin resistance remains a major therapeutic challenge leading to poor survival prognosis and treatment failure in breast cancer. Although doxorubicin induces massive changes in the transcriptional landscape are well known, potential diagnostic or therapeutic targets associated with the reorganization of three-dimensional (3D) chromatin architecture have not yet been systematically investigated. Methods: Here we performed in situ high-throughput chromosome conformation capture (Hi-C) on parental and doxorubicin-resistant MCF7 (MCF7-DR) human breast cancer cells, followed by integrative analysis of HiC, ATAC-seq, RNA-seq and TCGA data. Results: It revealed that A/B compartment switching was positively correlated to genome-wide differential gene expression. The genome of MCF7-DR cells was spatially reorganized into smaller topologically associating domains (TADs) and chromatin loops. We also revealed the contribution of increased chromatin accessibility and potential transcription factor families, including CTCF, AP-1 and bHLH, to gained TADs or loops. Intriguingly, we observed two condensed genomic regions (∼20 kb) with decreased chromatin accessibility flanking TAD boundaries, which might play a critical role in the formation or maintenance of TADs. Finally, combining data from TCGA, we identified a number of gained and lost enhancer-promoter interactions and their corresponding differentially expressed genes involved in chromatin organization and breast cancer signaling pathways, including FA2H, FOXA1 and JRKL, which might serve as potential treatment targets for breast cancer. Conclusion: These data uncovered a close connection between 3D genome reorganization, chromatin accessibility as well as gene transcription and provide novel insights into the epigenomic mechanisms involving doxorubicin resistance in breast cancer.
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Project description:We propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII) with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes ≥ 3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of specific mediators may offer a useful supplementary strategy to circumvent the effects of loss of endocrine sensitivity.
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Project description:Recent studies have clearly shown that long-range, three-dimensional chromatin looping interactions play a significant role in the regulation of gene expression, but whether looping is responsible for or a result of alterations in gene expression is still unknown. Until recently, how chromatin looping affects the regulation of gene activity and cellular function has been relatively ambiguous, and limitations in existing methods to manipulate these structures prevented in-depth exploration of these interactions. To resolve this uncertainty, we engineered a method for selective and reversible chromatin loop re-organization using CRISPR-dCas9 (CLOuD9). The dynamism of the CLOuD9 system has been demonstrated by successful localization of CLOuD9 constructs to target genomic loci to modulate local chromatin conformation. Importantly, the ability to reverse the induced contact and restore the endogenous chromatin conformation has also been confirmed. Modulation of gene expression with this method establishes the capacity to regulate cellular gene expression and underscores the great potential for applications of this technology in creating stable de novo chromatin loops that markedly affect gene expression in the contexts of cancer and development.
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Project description:We have discovered how Epstein-Barr virus (EBV) induces the reorganization of cellular chromatin (ROCC), in which host chromatin is compacted and marginated within the nucleus, with viral DNA replication occurring in the chromatin-free regions. Five families of DNA viruses induce ROCC: herpesviruses, adenoviruses, parvoviruses, baculoviruses, and geminiviruses. These families infect a variety of hosts, including vertebrates, insects, and plants. They also share several characteristics: they replicate and encapsidate their genomes in the host nucleus and package their genomes unbound by histones. We have identified the viral genes and processes required for EBV's ROCC. Each of EBV's seven core DNA synthesis genes and its origin of lytic replication (oriLyt), in trans, are required, while its protein kinase, BGLF4, and its true late genes are not. Following these findings, we tested the role of EBV lytic DNA amplification in driving ROCC. Surprisingly, the inhibition of EBV's lytic DNA synthesis still supports chromatin compaction but blocks its margination. We propose a two-step model for ROCC. First, the initiation of viral lytic DNA synthesis induces a cellular response that results in global chromatin compaction. Second, the histone-free, productive viral DNA synthesis leads to the margination of compacted chromatin to the nuclear periphery. We have tested this model by asking if the histone-associated simian virus 40 (SV40) DNA synthesis could substitute for oriLyt-mediated synthesis and found that EBV's ROCC is incompatible with SV40 DNA replication. Elucidating EBV's induction of ROCC both illuminates how other viruses can do so and indicates how this spatial control of cellular chromatin benefits them. IMPORTANCE Five families of viruses support the reorganization of cellular chromatin (ROCC), the compaction and margination of host chromatin, upon their productive infection. That they all share this phenotype implies the importance of ROCC in viral life cycles. With Epstein-Barr virus (EBV), a herpesvirus, we show that the viral replication complex and origin of lytic replication (oriLyt) are essential for ROCC. In contrast, its protein kinase and true late genes are not. We show that, unexpectedly, the viral lytic amplification is not required for chromatin compaction but is required for its margination. We propose a two-step model for ROCC: first, global chromatin compaction occurs as a cellular response to the initiation of viral DNA synthesis; then, the accumulation of newly synthesized, histone-free viral DNA leads to cellular chromatin margination. Taken together, our findings provide insights into a process contributing to the productive phase of five families of viruses.
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