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Reorganization of 3D chromatin architecture in doxorubicin-resistant breast cancer cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205874 | GEO | 2022/06/14

REPOSITORIES: GEO

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Project description:Three-dimensional genome structure plays an important role in gene regulation. Globally chromosomes are organized into active and inactive compartments, while at the gene level looping interactions connect promoters to regulatory elements. Topologically Associating Domains (TADs), typically several hundred kilobases in size form an intermediate level of organization. Major questions include how TADs are formed and what their relation is with looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb region on chromosome 7 surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Further, we find that these TAD boundaries are present irrespective of expression and looping of genes located between them. In contrast looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell type-specific long-range interactions and gene regulation. We investigated a 2.8 Mb region on Chromosome 7 (hg18 chr7: 115797757-118405450) containing the ENCODE region ENm001 42. The 5C experiment was designed to interrogate looping interactions between HindIII fragments containing transcription start sites (TSSs) and any other HindIII restriction fragment (distal fragments) in the target region. Libraries were generated for five cell lines: Caco2, Calu3, Capan1, GM12878 and HepG2, with two biological replicates for each line. 5C probes were designed at HindIII restriction sites (AAGCTT) using 5C primer design tools previously developed and made publicly available online at our My5C website (http://my5C.umassmed.edu). Probes were designed based on the ENCODE manual region 1 (ENM001) design 25 with additional probes placed throughout the region when appropriate. We also added probes to extend the analysis to include a 700 Kb gene desert region located directly adjacent to ENM001. Probe settings were: U-BLAST, 3; S-BLAST, 100; 15-MER, 3,000; MIN_FSIZE, 250; MAX_FSIZE, 20,000; OPT_TM, 65; OPT_PSIZE, 40. We designed 74 reverse 5C probes, and 605 forward 5C probes.