{"doi":"10.1126/sciadv.adf5330","title":"RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription","abstract":"<jats:p>Mixed-lineage leukemia 1 (MLL1) is a transcription activator of the HOX family, which binds to specific epigenetic marks on histone H3 through its third plant homeodomain (PHD3) domain. Through an unknown mechanism, MLL1 activity is repressed by cyclophilin 33 (Cyp33), which binds to MLL1 PHD3. We determined solution structures of Cyp33 RNA recognition motif (RRM) free, bound to RNA, to MLL1 PHD3, and to both MLL1 and the histone H3 lysine N6-trimethylated. We found that a conserved α helix, amino-terminal to the RRM domain, adopts three different positions facilitating a cascade of binding events. These conformational changes are triggered by Cyp33 RNA binding and ultimately lead to MLL1 release from the histone mark. Together, our mechanistic findings rationalize how Cyp33 binding to MLL1 can switch chromatin to a transcriptional repressive state triggered by RNA binding as a negative feedback loop.</jats:p>","journal":"Science Advances","year":2023,"id":649989,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1694708,"name":"Charlotte Meylan","orcid":"0000-0002-6982-8135","position":1,"is_corresponding":false},{"id":842511,"name":"Antoine Cléry","orcid":"0000-0002-4550-6908","position":2,"is_corresponding":false},{"id":832025,"name":"Roberto Giambruno","orcid":"0000-0002-4566-261X","position":3,"is_corresponding":false},{"id":1694709,"name":"Yaroslav Nikolaev","orcid":"0000-0002-1479-7474","position":4,"is_corresponding":false},{"id":1694710,"name":"Michel Heidecker","orcid":"0000-0002-3502-8607","position":5,"is_corresponding":false},{"id":1694711,"name":"Jessica Arvindbhai Solanki","orcid":null,"position":6,"is_corresponding":false},{"id":1153019,"name":"Manuel O. Dı́az","orcid":"0000-0003-2183-1535","position":7,"is_corresponding":false},{"id":658066,"name":"Davide Gabellini","orcid":"0000-0002-3811-4121","position":8,"is_corresponding":false},{"id":842512,"name":"Frédéric H.‐T. Allain","orcid":"0000-0002-2131-6237","position":9,"is_corresponding":false},{"id":1694707,"name":"Markus Blatter","orcid":"0000-0002-3643-9926","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription","abstract":"<jats:p>Mixed-lineage leukemia 1 (MLL1) is a transcription activator of the HOX family, which binds to specific epigenetic marks on histone H3 through its third plant homeodomain (PHD3) domain. Through an unknown mechanism, MLL1 activity is repressed by cyclophilin 33 (Cyp33), which binds to MLL1 PHD3. We determined solution structures of Cyp33 RNA recognition motif (RRM) free, bound to RNA, to MLL1 PHD3, and to both MLL1 and the histone H3 lysine N6-trimethylated. We found that a conserved α helix, amino-terminal to the RRM domain, adopts three different positions facilitating a cascade of binding events. These conformational changes are triggered by Cyp33 RNA binding and ultimately lead to MLL1 release from the histone mark. Together, our mechanistic findings rationalize how Cyp33 binding to MLL1 can switch chromatin to a transcriptional repressive state triggered by RNA binding as a negative feedback loop.</jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"37075125","pmcid":"PMC10115415","openalex_id":"https://openalex.org/W4366382685","authors":[],"funders":[{"funder_name":"Swiss National Science Foundation","grant_id":"189379","title":null},{"funder_name":"National Institutes of Health","grant_id":"1R21CA249378-01","title":"Regulation of human endogenous retroviruses in the context of cancer immunotherapy"},{"funder_name":"National Institutes of Health","grant_id":"5P01CA105049-05","title":"MLL-FUSIONS AND COOPERATING MUTATIONS IN ACUTE LEUKEMIA"},{"funder_name":"European Commission","grant_id":"267264","title":"INternational VEnue for poSTgraduate education"},{"funder_name":"Swiss National Science Foundation","grant_id":"123666","title":"Extracellular Matrix Remodeling and Angiogenesis in Cardiac Hypertrophy"}],"total_grants":5,"fwci":0.2782,"citation_percentile":0.49260377,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1126/sciadv.adf5330","host_type":"journal"},{"url":"https://doi.org/10.1126/sciadv.adf5330","host_type":"publisher"},{"url":"https://www.science.org/doi/pdf/10.1126/sciadv.adf5330","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/37075125","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10115415","host_type":"repository"},{"url":"https://www.science.org/doi/10.1126/sciadv.adf5330","host_type":"repository"},{"url":"http://hdl.handle.net/20.500.11850/609696","host_type":"repository"},{"url":"https://doi.org/10.3929/ethz-b-000609696","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10115415/pdf/sciadv.adf5330.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10115415","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10115415?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.3929/ethz-b-000609696","host_type":""},{"url":"http://dx.doi.org/10.1126/sciadv.adf5330","host_type":""},{"url":"https://hdl.handle.net/20.500.14243/460127","host_type":""},{"url":"http://www.scopus.com/record/display.url?eid=2-s2.0-85152980600&origin=inward","host_type":""}],"fields_of_study":["Signaling Pathways in Disease","RNA Research and Splicing","Genomics and Chromatin Dynamics","0301 basic medicine","03 medical and health sciences"],"mesh_terms":["DNA-Binding Proteins","Histones","Humans","Leukemia","Histone-Lysine N-Methyltransferase","RNA","Myeloid-Lymphoid Leukemia Protein"],"keywords":["Biology","Transcription (linguistics)","RNA","Histone H3","Histone","Chromatin","Allosteric regulation","Genetics","Cell biology","DNA","Gene","Histones","DNA-Binding Proteins","Leukemia","Humans","Biomedicine and Life Sciences","Histone-Lysine N-Methyltransferase","MLL1","transcription","RNA binding protein","Myeloid-Lymphoid Leukemia Protein"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T04:39:06.912855Z","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":[]}