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Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [Hi-C]

ABSTRACT: Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. However, little is known about the rewiring of the 3D chromatin landscape during cancer progression to a chemotherapy-resistant state. We utilized a patient-derived xenograft (PDX) mouse model of triple-negative breast cancer (UCD52) to characterize changes in the 3D structure between the primary tumor and carboplatin-resistant state. Systematic integration of matched chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing data revealed a widespread increase in short-range (<2Mb) interactions with the corresponding increase in chromatin looping and topologically associating domain (TAD) formation, chromatin state switching into a more active state, large-scale deletions, amplification of ATP-binding cassette (ABC) transporters and nearly complete shutdown of drug metabolism pathways. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of many aggressiveness-, metastasis- and other cancer-related pathways. Transcriptome changes suggest the role of downregulated protein-coding genes and upregulated long-noncoding RNAs in drug resistance. Integrative analysis confirmed increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial metabolic processes. Our results highlight that 3D genome remodeling may be a key mechanism underlying drug resistance.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE201428 | GEO | 2023/04/06

REPOSITORIES: GEO

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Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [RNA-Seq]

Project description:Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. However, little is known about the rewiring of the 3D chromatin landscape during cancer progression to a chemotherapy-resistant state. We utilized a patient-derived xenograft (PDX) mouse model of triple-negative breast cancer (UCD52) to characterize changes in the 3D structure between the primary tumor and carboplatin-resistant state. Systematic integration of matched chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing data revealed a widespread increase in short-range (<2Mb) interactions with the corresponding increase in chromatin looping and topologically associating domain (TAD) formation, chromatin state switching into a more active state, large-scale deletions, amplification of ATP-binding cassette (ABC) transporters and nearly complete shutdown of drug metabolism pathways. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of many aggressiveness-, metastasis- and other cancer-related pathways. Transcriptome changes suggest the role of downregulated protein-coding genes and upregulated long-noncoding RNAs in drug resistance. Integrative analysis confirmed increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial metabolic processes. Our results highlight that 3D genome remodeling may be a key mechanism underlying drug resistance.

2023-04-06 | GSE201434 | GEO

3D chromatin structure in colon cancer

Project description:We report the application of in situ Hi-C technology to 40 colorectal cancer patients and 10 paired-normal tissue to identify CRC specific changes in 3D chromatin structure. The chromatin contact matrices were generated by the sequencing data and image processing/deep learning-based algorithm was proposed to identify long-range abnormal chromatin interaction patterns in the contact matrices. The tumor specific 3D chromatin structure changes and the enhancer-promoter rewiring mediated by the identified chromatin structure changes were analyzed. The complex chromosome-wide rearrangements such as chromothripsis and its effect to 3D chromatin structure were also observed.

2023-07-27 | GSE137188 | GEO

Structural variants drive context dependent oncogene activation in cancer

Project description:Higher order chromatin structure is important for regulation of genes by distal regulatory sequences. Structural variants that alter 3D genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer. However, only a small minority of structural variants are associated with altered gene expression and it remains unclear why certain structural variants lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analyzing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as MYC, TERT, and CCND1. Using CRISPR/Cas9 genome engineering to generate de novo structural variants, we show that oncogene activity can be predicted using “Activity-by-Contact” models that consider partner region chromatin contacts and enhancer activity. However, Activity-by-Contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that structural variants that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of structural variants on oncogene activation.

2022-10-04 | GSE147123 | GEO

Single-cell 3D genome structure reveals distinct human pluripotent states (ATAC-Seq)

Project description:Pluripotent states of embryonic stem cells (ESCs) with distinct transcription profile affect their differentiation capacity and therapeutic potential. By single cell analysis of high-resolution three-dimensional (3D) genome structure, we show that remodeling genome structure is highly associated with pluripotent states of human ESCs (hESCs). Naive pluripotent state is featured with specialized 3D genome structures and clear chromatin compartmentation distinct from primed state. Naive pluripotent state may be achieved by remodeled active euchromatin compartment and less chromatin interaction in the nuclear center. This unique genome organization is linked to elevated chromatin accessibility on enhancers and thus high expression levels of naive pluripotent genes localized in this region. On the contrary, primed state exhibits intermingled genome organization. Moreover, active euchromatin and primed pluripotent genes are distributed in the nuclear periphery and yet repressive heterochromatin densely concentrated in the nuclear center, reducing chromatin accessibility and transcription of naive genes. Thus, inversion or relocation of heterochromatin to euchromatin compartmentation is related to regulating chromatin accessibility and thus define pluripotent states and cell identity.

2024-03-11 | GSE260991 | GEO

Single-cell 3D genome structure reveals distinct human pluripotent states (RNA-Seq)

2024-03-11 | GSE260994 | GEO

Single-cell 3D genome structure reveals distinct human pluripotent states (CUT&Tag-seq)

2024-03-11 | GSE260993 | GEO

Temporal dynamic reorganization of 3D chromatin in hormone-induced breast cancer and endocrine resistance [T47D]

Project description:To establish a data-driven learning model of the temporal dynamics and 3D chromatin reorganization, we conducted tethered chromatin conformation (TCC) sequencing to examine 3D structure dynamics in estradiol (E2)-induced breast cancer T47D cells and Tamoxifen resistant breast cancer T47D cells.

2019-04-09 | GSE119890 | GEO

Temporal dynamic reorganization of 3D chromatin in hormone-induced breast cancer and endocrine resistance

Project description:To establish a data-driven learning model of the temporal dynamics and 3D chromatin reorganization, we conducted tethered chromatin conformation (TCC) sequencing to examine 3D structure dynamics in estradiol (E2)-induced breast cancer MCF7 cells and Tamoxifen resistant breast cancer MCF7 cells.

2019-04-09 | GSE108787 | GEO

Global Reorganization of Chromatin Architecture during Embronic Stem Cell Differentiation

Project description:The 3D organization of the genome is important for regulation of diverse nuclear processes ranging from transcription to DNA replication. Knowledge of the higher order chromatin structure is critical for understanding mechanisms of gene regulation by long-range control elements such as enhancers and insulators. We describe high resolution, genome-wide dynamic chromatin interaction maps in human embryonic stem cells (hESC) as they differentiate into four distinct embryonic cell lineages. Extensive reorganization of higher-order chromatin structure occurs during hESC differentiation. In this process, topological domains remain largely intact but inter-domain association patterns change dramatically, coincident with widespread changes in chromatin state and gene expression. Moreover, using proximity ligation sequencing to generate chromosome span haplotypes, widespread allele biased gene activities are detected. The allelic gene expression patterns can be correlated to epigenetic state at distal enhancers, supporting the role of these elements in regulating gene expression over a distance. Two biological replicates of Hi-C experiment and one replicate of CTCF ChIP-Seq experiment in embryonic stem cells and 4 other differentiated cell-types from H1 cell line. Re-analysis of data from GSE16256 in an allele specific manner is linked as supplementary data.

2015-02-18 | E-GEOD-52457 | biostudies-arrayexpress

Cooperation of chromatin remodeling SWI/SNF complex and pioneer factor AP1 shapes 3D enhancer landscapes [Histone_modification]

Project description:The mechanism controlling the dynamic targeting of SWI/SNF has long been postulated to be coordinated by transcription factors (TFs), yet identifying and demonstrating the influence of different TFs has proven difficult. In this study we take a multi-omics approach to directly interrogate transient SWI/SNF interactors, chromatin targeting, and the plasticity of the resulting 3D epigenetic landscape. We utilized the novel proximity based labeling technique TurboID to identify the AP1 family as a critical interacting partner for endogenous SWI/SNF complexes. Validation through CUT&RUN profiling demonstrated SWI/SNF targeting enrichment at AP1 bound loci, and SWI/SNF – AP1 cooperation in chromatin targeting. Mapping of 3D chromatin structure via HiChIP revealed AP1-SWI/SNF dependent restructuring of promoter-enhancer architecture and generation of enhancer hubs, ultimately regulating transcription. Through direct interrogation of the SWI/SNF – AP1 interaction, we demonstrate a SWI/SNF functional dependency on AP1 mediated chromatin localization. We propose that pioneer factors such as AP1 bind and target SWI/SNF to inactive chromatin, where it restructures the genomic landscape into an active state through epigenetic rewiring spanning multiple dimensions.

2022-10-17 | GSE175530 | GEO

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