Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes
Abstract Background Genetic studies have associated thousands of enhancers with breast cancer (BC). However, the vast majority have not been functionally characterized. Thus, it remains unclear how BC-associated enhancers contribute to cancer. Results Here, we perform single-cell CRISPRi screens of...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Genome Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13059-025-03474-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594706494652416 |
|---|---|
| author | Yihan Wang Daniel A. Armendariz Lei Wang Huan Zhao Shiqi Xie Gary C. Hon |
| author_facet | Yihan Wang Daniel A. Armendariz Lei Wang Huan Zhao Shiqi Xie Gary C. Hon |
| author_sort | Yihan Wang |
| collection | DOAJ |
| description | Abstract Background Genetic studies have associated thousands of enhancers with breast cancer (BC). However, the vast majority have not been functionally characterized. Thus, it remains unclear how BC-associated enhancers contribute to cancer. Results Here, we perform single-cell CRISPRi screens of 3513 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of > 500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of BC-associated enhancers disrupts breast cancer gene programs. We observe BC-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple BC-associated enhancers indirectly regulate TP53. Comparative studies illustrate subtype specific functions between enhancers in ER + and ER − cells. Finally, we develop the pySpade package to facilitate analysis of single-cell enhancer screens. Conclusions Overall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development. |
| format | Article |
| id | doaj-art-8f7c06eda8bf4e57a1f6a565ad4cfd3c |
| institution | Kabale University |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj-art-8f7c06eda8bf4e57a1f6a565ad4cfd3c2025-01-19T12:25:36ZengBMCGenome Biology1474-760X2025-01-0126113610.1186/s13059-025-03474-0Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genesYihan Wang0Daniel A. Armendariz1Lei Wang2Huan Zhao3Shiqi Xie4Gary C. Hon5Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical CenterCecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical CenterCecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical CenterCecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical CenterCecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical CenterCecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical CenterAbstract Background Genetic studies have associated thousands of enhancers with breast cancer (BC). However, the vast majority have not been functionally characterized. Thus, it remains unclear how BC-associated enhancers contribute to cancer. Results Here, we perform single-cell CRISPRi screens of 3513 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of > 500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of BC-associated enhancers disrupts breast cancer gene programs. We observe BC-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple BC-associated enhancers indirectly regulate TP53. Comparative studies illustrate subtype specific functions between enhancers in ER + and ER − cells. Finally, we develop the pySpade package to facilitate analysis of single-cell enhancer screens. Conclusions Overall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development.https://doi.org/10.1186/s13059-025-03474-0EnhancersFunctional genomicsCancer genomicsRegulatory networksBreast cancerSingle-cell |
| spellingShingle | Yihan Wang Daniel A. Armendariz Lei Wang Huan Zhao Shiqi Xie Gary C. Hon Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes Genome Biology Enhancers Functional genomics Cancer genomics Regulatory networks Breast cancer Single-cell |
| title | Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes |
| title_full | Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes |
| title_fullStr | Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes |
| title_full_unstemmed | Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes |
| title_short | Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes |
| title_sort | enhancer regulatory networks globally connect non coding breast cancer loci to cancer genes |
| topic | Enhancers Functional genomics Cancer genomics Regulatory networks Breast cancer Single-cell |
| url | https://doi.org/10.1186/s13059-025-03474-0 |
| work_keys_str_mv | AT yihanwang enhancerregulatorynetworksgloballyconnectnoncodingbreastcancerlocitocancergenes AT danielaarmendariz enhancerregulatorynetworksgloballyconnectnoncodingbreastcancerlocitocancergenes AT leiwang enhancerregulatorynetworksgloballyconnectnoncodingbreastcancerlocitocancergenes AT huanzhao enhancerregulatorynetworksgloballyconnectnoncodingbreastcancerlocitocancergenes AT shiqixie enhancerregulatorynetworksgloballyconnectnoncodingbreastcancerlocitocancergenes AT garychon enhancerregulatorynetworksgloballyconnectnoncodingbreastcancerlocitocancergenes |