{"doi":"10.1101/2024.02.20.581236","title":"Cellular heterogeneity in the developing forebrain masks transcriptional outcomes and principles of <i>Evf2</i> enhancer lncRNA- <i>Dlx5/6UCE</i> -gene guidance","abstract":"Abstract During mouse embryonic brain development, the Evf2 ultraconserved enhancer (UCE) lncRNA guides the Dlx5/6UCE to ∼129 sites across chr6. However, previous work identified only 4 transcriptionally regulated targets associated with Evf2 -Dlx5/6UCE enhancer-gene guided sites (EGGs), raising questions about the significance of the majority of Evf2 -EGGs. Here, single cell transcriptomics (scRNAseq) shows that Evf2 -EGGs on chr6 coincide with subpopulation-specific Evf2 transcriptional targets, revealing far greater alignment between EGGs and transcriptional targets than previously reported. Surprisingly, subpopulation-specific Evf2 regulated gene networks in embryonic progenitors predict adult synaptic and seizure defects. Evf2 regulation of EGGs to gene bodies (GB, Dlx5/6UCE locations within ±5kb of the target gene) divides chr6 into short-range (&lt;10Mb distant), highly activated genes, and long/super-long-range (10-129Mb), moderately repressed genes. Clustering of Evf2 transcriptionally regulated chr6 targets in populations where Evf2 is first activated supports that Evf2 -EGG transcriptional effects can occur from EGG shifts as far as 3Mb, uncoupling enhancer shift distance and transcriptional direction from transcriptional outcome. Evf2 RNA binding sites (RBSs) divide chr6 into 4 major regions, consistent with a role for RBS chromosomal spacing in long-and super-long-range EGG selectivity. Surprisingly, 95% of 147 RBSs genome-wide potentially form inter-chromosomal DNA loops. Evf2 -regulated combinatorial recruitment of Evf2 -ribonucleoproteins at EGGs and RBSs, together with effects on homeodomain transcription factor DNA motif recognition, support a novel model of lncRNA directed multi-modal EGG selectivity during intra- and inter-chromosomal gene regulation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":494659,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":586038,"name":"Abhijit Chakraborty","orcid":"0000-0002-1500-3699","position":1,"is_corresponding":false},{"id":1341094,"name":"Sara Kohtz","orcid":"0000-0001-8333-6797","position":2,"is_corresponding":false},{"id":723883,"name":"Ivelisse Cajigas","orcid":null,"position":3,"is_corresponding":false},{"id":558747,"name":"Fion Shiau","orcid":"0000-0003-0848-6562","position":4,"is_corresponding":false},{"id":230263,"name":"Robert Vassar","orcid":"0000-0002-1358-504X","position":5,"is_corresponding":false},{"id":258261,"name":"Brian S. Clark","orcid":"0000-0002-7291-2055","position":6,"is_corresponding":false},{"id":723329,"name":"Jhumku D. Kohtz","orcid":"0000-0002-3483-5140","position":7,"is_corresponding":false},{"id":334863,"name":"Edward Li","orcid":"0000-0001-8661-0560","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:09:11.736910Z","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":[]}