{"doi":"10.64898/2025.12.23.696275","title":"Mdig shapes 3D chromatin architecture of immune checkpoint genes and limits metastasis of triple negative breast cancer cells","abstract":"Abstract Despite decades of progress in metastasis research, the identity of bona fide metastasis-driving genes remains elusive. By shifting the focus from individual genes to the three-dimensional (3D) architecture of the genome, we identify the mineral dust-induced gene (mdig) as a chromatin-topology regulator that suppresses immune-checkpoint activation and metastasis in triple-negative breast cancer (TNBC). Re-expression of mdig in mdig-knockout (KO) cells markedly reduced liver metastasis, whereas mdig loss activated epithelial-mesenchymal transition (EMT), T-cell exhaustion, and antigen-presentation pathways. Across multiple cancer types, high mdig expression predicted improved responses to immune checkpoint blockade (ICB). Mechanistically, mdig depletion derepressed inhibitory checkpoint genes, including PD-L1, PD-L2, LGALS9, and PLXNB1/2, accompanied by increased H3K9me3 and H3K36me3 at these loci. Hi-C profiling revealed that mdig maintains topologically associating domains (TADs) and long-range repressive loops at checkpoint loci; loss of mdig disrupted these structures, enabling coordinated activation of immune-evasion programs. Genome-wide analyses showed extensive TAD remodeling in mdig KO cells, with pronounced alterations on chromosome X. Collectively, these findings position mdig as a key chromatin-architectural regulator of immune evasion and metastatic behavior, underscoring its potential as a biomarker for ICB responsiveness in TNBC and beyond. Significance statement Metastasis remains the leading cause of cancer mortality, yet bona fide metastasis-driving genes remain difficult to define. By examining three-dimensional genome architecture rather than individual gene function, we identify mdig as a chromatin-topology regulator that restrains immune evasion and metastasis in triple-negative breast cancer. Loss of mdig disrupts TAD structures and long-range repressive loops at immune-checkpoint loci, enabling coordinated activation of EMT, antigen-presentation, and T-cell-exhaustion programs. Restoring mdig expression markedly reduces liver metastasis, and high mdig levels across cancers predict improved responses to immune-checkpoint blockade. These findings establish mdig as a key regulator of chromatin organization and a potential biomarker for immunotherapy responsiveness.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":587148,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9434,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"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":1396887,"name":"Ziqi Liu","orcid":"0000-0002-0977-2141","position":1,"is_corresponding":false},{"id":73955,"name":"Chitra Thakur","orcid":"0000-0002-4356-2543","position":2,"is_corresponding":false},{"id":1502220,"name":"Yiran Qiu","orcid":"0009-0002-9896-7086","position":3,"is_corresponding":false},{"id":6308,"name":"Jun Wang","orcid":"0000-0003-2509-9599","position":4,"is_corresponding":false},{"id":256176,"name":"Mehdi Damaghi","orcid":"0000-0002-7744-6161","position":5,"is_corresponding":false},{"id":1502759,"name":"John D Haley","orcid":null,"position":6,"is_corresponding":false},{"id":249437,"name":"Fei Chen","orcid":"0000-0002-7827-7988","position":7,"is_corresponding":false},{"id":830017,"name":"Ziwei Wang","orcid":"0000-0003-4135-3024","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T02:59:36.020030Z","pmid":null,"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":[]}