Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain
Abstract Background Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underli...
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | BMC Medical Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12920-020-0695-0 |
| _version_ | 1829464135584186368 |
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| author | Wesley L. Cai Celeste B. Greer Jocelyn F. Chen Anna Arnal-Estapé Jian Cao Qin Yan Don X. Nguyen |
| author_facet | Wesley L. Cai Celeste B. Greer Jocelyn F. Chen Anna Arnal-Estapé Jian Cao Qin Yan Don X. Nguyen |
| author_sort | Wesley L. Cai |
| collection | DOAJ |
| description | Abstract Background Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear. Methods To identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers. Results Our integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2. Using ATAC-seq, we identified a metastasis open-chromatin signature that is elevated in basal-like and HER2-enriched breast cancer subtypes and associates with worse prognosis in human samples. We further uncovered TFs associated with the open chromatin landscapes of metastatic cells and whose expression correlates with risk for metastasis. While some of these TFs are associated with primary breast tumor subtypes, others more specifically correlate with lung or brain metastasis. Conclusions We identify distinctive epigenomic properties of breast cancer cells that metastasize to the lung and brain. We also demonstrate that signatures of active chromatin sites are partially linked to human breast cancer subtypes with poor prognosis, and that specific TFs can independently distinguish lung and brain relapse. |
| first_indexed | 2024-12-13T13:42:50Z |
| format | Article |
| id | doaj.art-ab87df052f1042da9558ebcc14ccc2e6 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-13T13:42:50Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-ab87df052f1042da9558ebcc14ccc2e62022-12-21T23:43:32ZengBMCBMC Medical Genomics1755-87942020-03-0113111810.1186/s12920-020-0695-0Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brainWesley L. Cai0Celeste B. Greer1Jocelyn F. Chen2Anna Arnal-Estapé3Jian Cao4Qin Yan5Don X. Nguyen6Department of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineAbstract Background Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear. Methods To identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers. Results Our integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2. Using ATAC-seq, we identified a metastasis open-chromatin signature that is elevated in basal-like and HER2-enriched breast cancer subtypes and associates with worse prognosis in human samples. We further uncovered TFs associated with the open chromatin landscapes of metastatic cells and whose expression correlates with risk for metastasis. While some of these TFs are associated with primary breast tumor subtypes, others more specifically correlate with lung or brain metastasis. Conclusions We identify distinctive epigenomic properties of breast cancer cells that metastasize to the lung and brain. We also demonstrate that signatures of active chromatin sites are partially linked to human breast cancer subtypes with poor prognosis, and that specific TFs can independently distinguish lung and brain relapse.http://link.springer.com/article/10.1186/s12920-020-0695-0ATAC-seqChIP-seqBreast cancerMetastasisTranscription factorsEpigenomics |
| spellingShingle | Wesley L. Cai Celeste B. Greer Jocelyn F. Chen Anna Arnal-Estapé Jian Cao Qin Yan Don X. Nguyen Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain BMC Medical Genomics ATAC-seq ChIP-seq Breast cancer Metastasis Transcription factors Epigenomics |
| title | Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain |
| title_full | Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain |
| title_fullStr | Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain |
| title_full_unstemmed | Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain |
| title_short | Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain |
| title_sort | specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain |
| topic | ATAC-seq ChIP-seq Breast cancer Metastasis Transcription factors Epigenomics |
| url | http://link.springer.com/article/10.1186/s12920-020-0695-0 |
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