{"doi":"10.1186/s13059-025-03474-0","title":"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 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.","journal":"Genome biology","year":2025,"id":516896,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9379,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":284864,"name":"Daniel Armendariz","orcid":"0000-0002-5857-1282","position":1,"is_corresponding":false},{"id":464124,"name":"Lei Wang","orcid":"0009-0005-0050-0691","position":2,"is_corresponding":false},{"id":1168345,"name":"Huan Zhao","orcid":"0000-0001-6824-1570","position":3,"is_corresponding":false},{"id":995092,"name":"Shiqi Xie","orcid":"0000-0002-0516-3621","position":4,"is_corresponding":false},{"id":3800,"name":"Gary C. Hon","orcid":"0000-0002-5728-4433","position":5,"is_corresponding":false},{"id":995091,"name":"Yihan Wang","orcid":"0000-0002-0839-0707","position":0,"is_corresponding":true}],"reference_count":150,"raw_metadata":null,"created_at":"2026-07-19T02:48:54.768083Z","pmid":"39825430","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}