Integrated chromatin accessibility and transcriptome landscapes of doxorubicin-resistant breast cancer cells
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ABSTRACT:
PROVIDER: PRJNA728600 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14479966_1.fastq.gz | Fastqsanger.gz | |||
| SRR14479966_2.fastq.gz | Fastqsanger.gz | |||
| SRR14479967_1.fastq.gz | Fastqsanger.gz | |||
| SRR14479967_2.fastq.gz | Fastqsanger.gz | |||
| SRR14479968_1.fastq.gz | Fastqsanger.gz |
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Project description:Doxorubicin is considered to be the most effective chemotherapeutic drug used to treat breast cancer. Unfortunately, resistance to this drug is common, resulting in poor patient prognosis and survival. Dynamically reorganized chromatin allows rapid access of the gene regulatory machinery to open genomic regions facilitating subsequent gene expression through direct transcription factor (TF) activation and regulatory element binding. To better understand the regulatory network underlying doxorubicin resistance in breast cancer cells, we explored the systematic alterations of chromatin accessibility and gene expression by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with RNA sequencing, followed by integrative analysis to identify potential regulators and their targets associated with differentially accessible regions (DARs) in doxorubicin-resistant MCF7 (MCF7-DR) cells. A total of 3963 differentially expressed genes (DEGs) related to doxorubicin resistance were identified, including dramatically up-regulated MT1E, GSTP1, LDHB, significantly down-regulated TFF1, UBB, DSCAM-AS1, and histone-modifying enzyme coding genes HDAC2, EZH2, PRMT5, etc. By integrating with transcriptomic datasets, we identified 18,228 DARs in MCF7-DR cells compared to control, which were positively (r = 0.6) correlated with their nearest DEGs. There were 11,686 increased chromatin-accessible regions, which were enriched in up-regulated genes related to diverse KEGG pathways, such as the cell cycle, regulation of actin cytoskeleton, signaling pathways of MAPK, PI3K/Akt and Hippo, which play essential roles in regulating cell apoptosis, proliferation, metabolism, and inflammatory responses. The 6,542 decreased chromatin-accessible regions were considered to be related to declined doxorubicin-associated biological processes, for instance, endocrine and insulin resistance, central carbon metabolism, signaling pathways of TGF-beta and P53. Analyses of the DAR sequences showed that, besides the AP-1 family, TEAD and FOX family TF DNA-binding motifs were highly enriched in hyper- and hypo-accessible regions respectively. Moreover, critical TFs and their potential targets associated with DARs were identified, such as TEAD1, RUNX1, GRHL2 and FOXA1. In addition, we put forward that the loss of FOXA1/GRHL2 collaboration might be responsible for acquired resistance to doxorubicin in breast cancer. These data provided clear insights and resources for an improved understanding of the non-genetic landscape of doxorubicin-resistant breast cancer cells based on chromatin accessibility and transcript levels, which allowed for detection of critical TFs, potential cis-regulatory elements, and therapeutic targets.
2021-05-12 | GSE174152 | GEO
Project description:BackgroundDoxorubicin is one of the most effective chemotherapeutic drugs for breast cancer while its common drug resistance leads to poor patient prognosis and survival. Growing evidence indicate dynamically reorganized chromatin allows rapid access of the gene regulatory machinery to open genomic regions facilitating subsequent gene expression through direct transcription factor (TF) activation and regulatory element binding.MethodsTo better understand the regulatory network underlying doxorubicin resistance in breast cancer cells, we explored the systematic alterations of chromatin accessibility and gene expression by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with RNA sequencing, followed by integrative analysis to identify potential regulators and their targets associated with differentially accessible regions (DARs) in doxorubicin-resistant MCF7 (MCF7-DR) cells.ResultsA total of 3,963 differentially expressed genes (DEGs) related to doxorubicin resistance were identified, including dramatically up-regulated MT1E, GSTP1, LDHB, significantly down-regulated TFF1, UBB, DSCAM-AS1, and histone-modifying enzyme coding genes HDAC2, EZH2, PRMT5, etc. By integrating with transcriptomic datasets, we identified 18,228 DARs in MCF7-DR cells compared to control, which were positively correlated with their nearest DEGs (r = 0.6). There were 11,686 increased chromatin-accessible regions, which were enriched in up-regulated genes related to diverse KEGG pathways, such as the cell cycle, regulation of actin cytoskeleton, signaling pathways of MAPK, PI3K/Akt and Hippo, which play essential roles in regulating cell apoptosis, proliferation, metabolism, and inflammatory responses. The 6,542 decreased chromatin-accessible regions were identified for the declined doxorubicin-associated biological processes, for instance, endocrine and insulin resistance, central carbon metabolism, signaling pathways of TGF-beta and P53. Combining data from TCGA, analyses of the DAR sequences associated with the DNA-binding motifs of significantly enriched TF families including AP-1, TEAD and FOX, indicated that the loss-function of FOXA1 might play a critical role in doxorubicin-resistant breast cancer cells (DOX-R BCCs).ConclusionThese data exhibit the non-genetic landscape of chromatin accessibility and transcript levels in the DOX-R BCCs, and provide clear insights and resources for the detection of critical TFs and potential cis-regulatory elements-based putative therapeutic targets.
| S-EPMC8363264 | biostudies-literature
Project description:Integrated chromatin accessibility and transcriptome landscapes of 5-Fluorouracil-resistant colon cancer cells
| PRJNA789176 | ENA
Project description:Doxorubicin resistance remains a major therapeutic challenge leading to treatment failure and poor survival prognosis in breast cancer. Although doxorubicin induces massive changes in the transcriptional landscape accompanied by alterations of chromatin accessibility are well known, potential diagnostic or therapeutic targets associated with three-dimensional (3D) genome reorganization in doxorubicin-resistant breast cancer cells have not yet been systematically investigated. Here we performed integrated analyses combining in situ high-throughput chromosome conformation capture (Hi-C), ATAC-seq and mHi-C data on doxorubicin-resistant MCF7 human breast cancer cells compared to parental cells. It revealed that A/B compartment switching was positively correlated to genome-wide differential gene expression, and the genome was spatially reorganized into smaller topologically associating domains (TADs) and loops. We also revealed the contribution of increased chromatin accessibility and potential transcription factor families, including CTCF and BORIS, to gained TAD boundaries and loop anchors. Intriguingly, we observed two condensed genomic regions (~20kb) with decreased chromatin accessibility flanking TAD boundaries, which might play a critical role in the formation or maintenance of TADs. Moreover, we identified a number of gained and lost enhancer-promoter interactions associated with differentially expressed genes, including FA2H, FOXA1, JRKL and EZH, some of which involved in chromatin organization and breast cancer signaling pathways. This study uncovered a close connection between 3D genome reorganization, chromatin accessibility as well as gene transcription, and provides resources and novel insights into the epigenomic mechanisms with potential therapeutic implications for doxorubicin resistance in breast cancer.
2022-06-14 | GSE205874 | GEO
Project description:Chromatin accessibility landscapes across B-ALL
| PRJNA871228 | ENA
Project description:Background: 5-Fluorouracil (5-FU) is one of the most effective and widely used chemotherapeutic drugs in the treatment of colon cancer, yet chemoresistance is a common feature of colon cancer treatment, resulting in poor prognosis and short survival. Dynamic reprogramming of chromatin accessibility is crucial for proper regulation of gene transcription associated with cancer drug resistance by providing the gene regulatory machinery with rapid access to the open genomic DNA. Methods: Here, we explored the global chromatin accessibility and transcription changes by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with transcriptome sequencing of both parental and 5-FU-resistant HCT15 cells, followed by integrative analysis to better understand the regulatory network underlying 5-FU resistance in colon cancer cells. Results: A total of 3,175 differentially expressed mRNAs (DEGs), lncRNAs (DELs), and miRNAs (DEMs) related to 5-FU resistance were identified, including significantly upregulated IL33, H19, and miR-17-5p; the downregulated AKR1B10, LINC01012, and miR-125b-5p; and chromatin modifiers such as INO80C, HDAC6, and KDM5A. The construction of the ceRNA regulatory network revealed that H19, HOXA11-AS, and NEAT1 might function as ceRNAs associated with 5-FU resistance in HCT15 cells. Moreover, 9,868 differentially accessible regions (DARs) were obtained, which were positively (r = 0.58) correlated with their nearest DEGs and DELs. The upregulated genes related to 4,937 hyper-accessible regions were significantly enriched in signaling pathways of MAPK, FOX, and WNT, while the 4,931 hypo-accessible regions were considered to be involved in declined biosynthesis of amino acids and nucleotide sugars, signaling pathways of Notch, and HIF-1. Analyses of the DAR sequences revealed that besides the AP-1 family, the TF motifs of FOX and KLF family members were highly enriched in hyper- and hypo-accessible regions, respectively. Finally, we obtained several critical TFs and their potential targets associated with DARs and 5-FU resistance, including FOXA1 and KLF3. Conclusion: These data provided clear insights and valuable resources for an improved understanding of the non-genetic landscape of 5-FU-resistant colon cancer cells based on chromatin accessibility and transcript levels, which allowed for genome-wide detection of TF binding sites, potential cis-regulatory elements and therapeutic targets.
| S-EPMC8891516 | biostudies-literature
Project description:5-Fluorouracil (5-FU) is one of the most effective and widely used chemotherapeutic drugs in the treatment of colon cancer. Yet chemoresistance is a common feature of colon cancer, resulting in poor prognosis and short survival. Dynamic reprogramming of chromatin accessibility allows rapid access of the gene regulatory machinery to open genomic regions facilitating subsequent gene expression via direct transcription factor activation and regulatory element-binding. To better understand the regulatory network underlying 5-FU resistance in colon cancer cells, we explored the systematic alterations of chromatin accessibility and transcript expression by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with transcriptome sequencing, followed by integrative analysis to identify potential regulators and their targets associated with differentially accessible regions (DARs) in 5-FU-resistant HCT15 (HCT15-FR) cells. A total of 3175 differentially expressed mRNAs (DEGs), lncRNAs (DELs) and miRNAs (DEMs) related to 5-FU resistance were identified, including dramatically up-regulated IL33, H19, miR-17-5p, significantly down-regulated AKR1B10, LINC01012, miR-125b-5p, and potential chromatin modifiers such as INO80C, HDAC6 and KDM5A. A competitive endogenous RNAs (ceRNAs) regulatory network was established based on information about interactions among DEGs, DELs and DEMs, suggesting that H19, HOXA11-AS and NEAT1 might function as ceRNAs associate with 5-FU resistance in HCT15 cells. By integrating with transcriptome data, 9868 DARs were identified in HCT15-FR cells compared to control, which were positively (r = 0.58) correlated with their nearest DEGs and DELs. The up-regulated genes related to 4937 increased chromatin-accessible regions were significantly enriched in signaling pathways of MAPK, FOX and WNT, while the 4931 decreased chromatin-accessible regions were considered to be involved in declined biosynthesis of amino acids and nucleotide sugars, signaling pathways of Notch, and HIF-1. Analyses of the DAR sequences revealed that, besides AP-1 family, the TF DNA-binding motifs of FOX and KLF family members were highly enriched in hyper- and hypo-accessible regions, respectively. Moreover, relationships of critical TFs and their potential targets associated with DARs were identified, such as FOXA1, RUNX2, KLF3 and GRHL2. These data provided clear insights and valuable resources for an improved understanding of the non-genetic landscape of 5-FU-resistant colon cancer cells based on chromatin accessibility and transcript levels, which allowed for genome-wide detection of TF-binding sites, potential cis-regulatory elements and therapeutic targets.
2021-12-17 | GSE190951 | GEO
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2019-01-17 | GSE125180 | GEO
Project description:Liver Chromatin accessibility landscapes during onset of salmon maturation
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Project description:Ovarian cancer is one of the most common cancer among women in the world, and chemotherapy remains the principal treatment for patients. However, drug resistance is a major obstacle to the effective treatment of ovarian cancers and the underlying mechanism is not clear. An increased understanding of the mechanisms that underline the pathogenesis of drug resistance is therefore needed to develop novel therapeutics and diagnostic. Herein, we report the comparative analysis of the doxorubicin sensitive OVCAR8 cells and its doxorubicin-resistant variant NCI/ADR-RES cells using integrated global proteomics and N-glycoproteomics. A total of 1525 unique N-glycosite-containing peptides from 740 N-glycoproteins were identified and quantified, of which 253 N-glycosite-containing peptides showed significant change in the NCI/ADR-RES cells. Meanwhile, stable isotope labeling by amino acids in cell culture (SILAC) based comparative proteomic analysis of the two ovarian cancer cells led to the quantification of 5509 proteins. As about 50% of the identified N-glycoproteins are low-abundance membrane proteins, only 44% of quantified unique N-glycosite-containing peptides had corresponding protein expression ratios. The comparison and calibration of the N-glycoproteome versus the proteome classified 14 change patterns of N-glycosite-containing peptides, including 8 up-regulated N-glycosite-containing peptides with the increased glycosylation sites occupancy, 35 up-regulated N-glycosite-containing peptides with the unchanged glycosylation sites occupancy, 2 down-regulated N-glycosite-containing peptides with the decreased glycosylation sites occupancy, 46 down-regulated N-glycosite-containing peptides with the unchanged glycosylation sites occupancy. Integrated proteomic and N-glycoproteomic analyses provide new insights, which can help to unravel the relationship of N-glycosylation and multidrug resistance (MDR), understand the mechanism of MDR, and discover the new diagnostic and therapeutic targets.
2019-02-15 | PXD012655 | Pride