{"doi":"10.1101/2020.07.23.218503","title":"Lineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation","abstract":"Abstract Temporal regulation of super-enhancer (SE) driven lineage specific transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability of sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify critical SEs driving TF regulators of NB, we utilized NB cells in which all-trans retinoic acid (ATRA) induces growth arrest and differentiation. H3K27ac ChIP-seq paired with RNA-seq over a time course of ATRA treatment revealed SEs moving in a coordinated manner with four distinct temporal patterns (clusters). SEs that decreased with ATRA linked to 24 TFs involved in stem cell development/specialization ( MYCN, GATA3, SOX11) along with LMO1 , a transcriptional coregulator and oncogene identified via a genome-wide association study (GWAS) of NB. H3K27ac levels and GATA3 binding at the NB-associated rs2168101 site of the LMO1 SE were reduced with ATRA treatment, resulting in 1.46 fold decreased LMO1 expression. The SOX11 SE was lost coincident with a 50% decrease in mRNA after 8 days of ATRA treatment. CRISPR-Cas9 screening and siRNA inhibition showed a dependency on SOX11 for cell growth in NB cell lines. Silencing of the SOX11 SE using dCAS9-KRAB targeted guides caused a 40% decrease in SOX11 mRNA and inhibited cell growth. Three other TF SE clusters had sequential waves of activation at 2, 4 and 8 days of ATRA treatment and involved TFs regulating neural development ( GATA2 and SOX4 ). Silencing of the gained SOX4 SE using dCAS9-KRAB targeting, caused a 50% decrease in SOX4 expression and attenuated expression of ATRA-induced differentiation genes. Our study has identified candidate oncogenic lineage drivers of NB self-renewal and TFs critical for implementing a differentiation program.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122209,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":316688,"name":"Berkley E. Gryder","orcid":"0000-0003-0130-2302","position":1,"is_corresponding":false},{"id":490908,"name":"Sukriti Bagchi","orcid":"0000-0003-3851-8182","position":2,"is_corresponding":false},{"id":563030,"name":"Zhihui Liu","orcid":"0000-0001-8650-9104","position":3,"is_corresponding":false},{"id":563914,"name":"Hsien-Chao Chen","orcid":null,"position":4,"is_corresponding":false},{"id":227611,"name":"Man Xu","orcid":"0000-0001-8449-1203","position":5,"is_corresponding":false},{"id":563031,"name":"Ming Sun","orcid":"0000-0002-6313-4458","position":6,"is_corresponding":false},{"id":32667,"name":"Zalman Vaksman","orcid":"0000-0001-5121-8657","position":7,"is_corresponding":false},{"id":32676,"name":"Sharon J. Diskin","orcid":"0000-0002-7200-8939","position":8,"is_corresponding":false},{"id":250453,"name":"Javed Khan","orcid":"0000-0002-5858-0488","position":9,"is_corresponding":false},{"id":399507,"name":"Carol J. Thiele","orcid":"0000-0003-2869-7690","position":10,"is_corresponding":false},{"id":563913,"name":"Deblina Banerjee","orcid":null,"position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-18T23:14:51.076430Z","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":[]}