{"doi":"10.1101/2021.09.20.461083","title":"Identification of topoisomerase as a precision-medicine target in chromatin reader SP140-driven Crohn’s disease","abstract":"Summary How mis-regulated chromatin directly impacts human immunological disease is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing chromatin ‘reader’ whose loss-of-function associates with Crohn’s disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). However, mechanisms underlying SP140-driven pathogenicity and therapeutic approaches that rescue SP140 remain unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOP) that maintains heterochromatin and immune cell fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, genome instability, severely compromised lineage-defining and microbe-inducible innate transcriptional programs and defective bacterial killing. Pharmacological inhibition of TOP1 or TOP2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1 or TOP2 inhibitors in Sp140 −/− mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a repressor of topoisomerases and reveal repurposing of TOP inhibition as a precision strategy for reversing SP140-driven immune disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":219350,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":818597,"name":"Sreehaas Digumarthi","orcid":null,"position":1,"is_corresponding":false},{"id":278756,"name":"Isabella Fraschilla","orcid":"0000-0002-4166-6293","position":2,"is_corresponding":false},{"id":467392,"name":"Fatemeh Adiliaghdam","orcid":"0000-0001-6184-6796","position":3,"is_corresponding":false},{"id":316331,"name":"Gracia Bonilla","orcid":null,"position":4,"is_corresponding":false},{"id":500244,"name":"Lai Ping Wong","orcid":null,"position":5,"is_corresponding":false},{"id":260528,"name":"Ruslan I. Sadreyev","orcid":"0000-0002-4240-5466","position":6,"is_corresponding":false},{"id":225191,"name":"Kate L. Jeffrey","orcid":"0000-0001-5746-0153","position":7,"is_corresponding":false},{"id":817931,"name":"Hajera Amatullah","orcid":"0000-0003-4575-831X","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:53:38.409982Z","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":[]}