{"doi":"10.1101/2023.03.07.531569","title":"Dynamic network-guided CRISPRi screen reveals CTCF loop-constrained nonlinear enhancer-gene regulatory activity in cell state transitions","abstract":"Comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Our network modeling revealed that nonlinear enhancer-gene regulation during cell state transitions can be leveraged to improve the sensitivity of enhancer discovery. Utilizing hESC definitive endoderm differentiation as a dynamic transition system, we conducted a mid-transition CRISPRi-based enhancer screen. The screen discovered a comprehensive set of enhancers (4 to 9 per locus) for each of the core endoderm lineage-specifying transcription factors, and many enhancers had strong effects mid-transition but weak effects post-transition. Through integrating enhancer activity measurements and three-dimensional enhancer-promoter interaction information, we were able to develop a CTCF loop-constrained Interaction Activity (CIA) model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Our study provides generalizable strategies for sensitive and more comprehensive enhancer discovery in both normal and pathological cell state transitions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392239,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"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":0.9444,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":998265,"name":"Jielin Yan","orcid":"0000-0001-9305-3942","position":1,"is_corresponding":false},{"id":1032102,"name":"Jin Woo Oh","orcid":"0000-0002-3545-5481","position":2,"is_corresponding":false},{"id":395306,"name":"Xi Wang","orcid":"0000-0002-7572-6354","position":3,"is_corresponding":false},{"id":1032713,"name":"Dustin Shigaki","orcid":null,"position":4,"is_corresponding":false},{"id":1032103,"name":"Wilfred Hing Sang Wong","orcid":"0000-0001-8396-2368","position":5,"is_corresponding":false},{"id":571171,"name":"Hyunwoo Cho","orcid":"0000-0003-3166-585X","position":6,"is_corresponding":false},{"id":329479,"name":"Dylan Murphy","orcid":"0000-0002-4368-8402","position":7,"is_corresponding":false},{"id":906850,"name":"Ronald Cutler","orcid":"0000-0001-7744-090X","position":8,"is_corresponding":false},{"id":632569,"name":"Bess P. Rosen","orcid":"0000-0003-1167-656X","position":9,"is_corresponding":false},{"id":632571,"name":"Julián Pulecio","orcid":"0000-0002-4455-8095","position":10,"is_corresponding":false},{"id":6098,"name":"Dapeng Yang","orcid":"0000-0001-8687-4486","position":11,"is_corresponding":false},{"id":1165497,"name":"Rachel Glenn","orcid":"0000-0003-1238-4905","position":12,"is_corresponding":false},{"id":975721,"name":"Tingxu Chen","orcid":"0000-0001-8781-3562","position":13,"is_corresponding":false},{"id":869565,"name":"Qing V. Li","orcid":"0000-0002-0087-9700","position":14,"is_corresponding":false},{"id":705189,"name":"Thomas Vierbuchen","orcid":"0000-0002-5690-5680","position":15,"is_corresponding":false},{"id":247704,"name":"Simone Sidoli","orcid":"0000-0001-9073-6641","position":16,"is_corresponding":false},{"id":56471,"name":"Effie Apostolou","orcid":"0000-0002-8111-0863","position":17,"is_corresponding":false},{"id":632575,"name":"Danwei Huangfu","orcid":"0000-0002-1145-6199","position":18,"is_corresponding":false},{"id":18712,"name":"Michael A. Beer","orcid":"0000-0001-9955-3809","position":19,"is_corresponding":false},{"id":254934,"name":"Renhe Luo","orcid":"0009-0008-1470-4726","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:52.232318Z","pmid":"36945628","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":[]}