{"doi":"10.1186/s13059-021-02498-6","title":"KrasG12D induces changes in chromatin territories that differentially impact early nuclear reprogramming in pancreatic cells","abstract":"Abstract Background Pancreatic ductal adenocarcinoma initiation is most frequently caused by Kras mutations. Results Here, we apply biological, biochemical, and network biology methods to validate GEMM-derived cell models using inducible Kras G12D expression. We describe the time-dependent, chromatin remodeling program that impacts function during early oncogenic signaling. We find that the Kras G12D -induced transcriptional response is dominated by downregulated expression concordant with layers of epigenetic events. More open chromatin characterizes the ATAC-seq profile associated with a smaller group of upregulated genes and epigenetic marks. RRBS demonstrates that promoter hypermethylation does not account for the silencing of the extensive gene promoter network. Moreover, ChIP-Seq reveals that heterochromatin reorganization plays little role in this early transcriptional program. Notably, both gene activation and silencing primarily depend on the marking of genes with a combination of H3K27ac, H3K4me3, and H3K36me3. Indeed, integrated modeling of all these datasets shows that Kras G12D regulates its transcriptional program primarily through unique super-enhancers and enhancers, and marking specific gene promoters and bodies. We also report chromatin remodeling across genomic areas that, although not contributing directly to cis-gene transcription, are likely important for Kras G12D functions. Conclusions In summary, we report a comprehensive, time-dependent, and coordinated early epigenomic program for Kras G12D in pancreatic cells, which is mechanistically relevant to understanding chromatin remodeling events underlying transcriptional outcomes needed for the function of this oncogene.","journal":"Genome biology","year":2021,"id":181573,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"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":732559,"name":"Romica Kerketta","orcid":"0000-0002-7007-1395","position":1,"is_corresponding":false},{"id":238785,"name":"Thiago M. de Assuncao","orcid":null,"position":2,"is_corresponding":false},{"id":733220,"name":"Elise Leverence","orcid":null,"position":3,"is_corresponding":false},{"id":733221,"name":"Atefeh Zeighami","orcid":null,"position":4,"is_corresponding":false},{"id":733222,"name":"Guillermo Urrutia","orcid":null,"position":5,"is_corresponding":false},{"id":428982,"name":"Timothy J. Stodola","orcid":"0000-0001-9671-884X","position":6,"is_corresponding":false},{"id":225422,"name":"Marina Pasca di Magliano","orcid":"0000-0001-9632-9035","position":7,"is_corresponding":false},{"id":594559,"name":"Juan Iovanna","orcid":"0000-0003-1822-2237","position":8,"is_corresponding":false},{"id":401670,"name":"Michael T. Zimmermann","orcid":"0000-0001-7073-0525","position":9,"is_corresponding":false},{"id":523901,"name":"Gwen Lomberk","orcid":"0000-0001-5463-789X","position":10,"is_corresponding":false},{"id":282811,"name":"Raúl Urrutia","orcid":"0000-0002-1640-6780","position":11,"is_corresponding":false},{"id":523900,"name":"Angela Mathison","orcid":"0000-0002-6763-2710","position":0,"is_corresponding":true}],"reference_count":97,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:48:05.146883Z","pmid":"34649604","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":[]}