{"doi":"10.1126/sciadv.abg7444","title":"The H3K36me2 writer-reader dependency in H3K27M-DIPG","abstract":"Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.","journal":"Science Advances","year":2021,"id":162358,"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":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"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":49844,"name":"Gary LeRoy","orcid":"0000-0002-0769-4944","position":1,"is_corresponding":false},{"id":402717,"name":"Devin Bready","orcid":"0000-0003-3557-2888","position":2,"is_corresponding":false},{"id":402715,"name":"Joshua D. Frenster","orcid":"0000-0003-2401-1575","position":3,"is_corresponding":false},{"id":678955,"name":"Ricardo Saldaña-Meyer","orcid":"0000-0001-8431-2682","position":4,"is_corresponding":false},{"id":678956,"name":"Ying Jin","orcid":"0000-0003-0070-2048","position":5,"is_corresponding":false},{"id":659008,"name":"Nicolas Descostes","orcid":"0000-0001-5599-5808","position":6,"is_corresponding":false},{"id":388872,"name":"James M. Stafford","orcid":"0000-0002-1435-6898","position":7,"is_corresponding":false},{"id":402724,"name":"Dimitris G. Placantonakis","orcid":"0000-0003-1950-2978","position":8,"is_corresponding":false},{"id":38290,"name":"Danny Reinberg","orcid":"0000-0003-4288-2016","position":9,"is_corresponding":false},{"id":678954,"name":"Jia-Ray Yu","orcid":"0000-0002-7080-4333","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:45:00.600065Z","pmid":"34261657","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":[]}