{"doi":"10.1093/g3journal/jkaf089","title":"A single high-zinc activation enhancer can control two genes oriented head-to-head in <i>Caenorhabditis elegans</i>","abstract":"Enhancers play critical roles in gene expression, but a full understanding of their complex functions has yet to be defined. The cellular response to excess zinc levels in Caenorhabditis elegans requires the HIZR-1 transcription factor, which binds the high-zinc activation (HZA) enhancer in the promoters of multiple target genes. Cadmium hijacks the excess zinc response by binding and activating HIZR-1. By analyzing the genome-wide transcriptional response to excess zinc and cadmium, we identified two positions in the genome where head-to-head oriented genes are both induced by metals. In both examples, a single predicted HZA enhancer is positioned between the two translational start sites. We hypothesized that a single enhancer can control both head-to-head genes, an arrangement that has not been extensively characterized. To test this hypothesis, we used CRISPR genome editing to precisely delete the HZAmT enhancer positioned between mtl-2 and T08G5.1; in this mutant, both head-to-head genes display severely reduced zinc-activated transcription, whereas zinc-activated transcription of more distant genes was not strongly affected. Deleting the HZAcF enhancer positioned between cdr-1 and F35E8.10 caused both head-to-head genes to display reduced cadmium-activated transcription, whereas cadmium-activated transcription of more distant genes was not strongly affected. These studies rigorously document that a single HZA enhancer can control two head-to-head genes, advancing our understanding of the diverse functions of enhancers.","journal":"G3 Genes Genomes Genetics","year":2025,"id":544369,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":363762,"name":"Brian Earley","orcid":"0000-0002-6707-6785","position":1,"is_corresponding":false},{"id":363763,"name":"Adelita D. Mendoza","orcid":"0000-0001-8152-3839","position":2,"is_corresponding":false},{"id":1434933,"name":"P. J. Hunt","orcid":null,"position":3,"is_corresponding":false},{"id":1434934,"name":"Sean Teng","orcid":null,"position":4,"is_corresponding":false},{"id":689144,"name":"Daniel L. Schneider","orcid":"0000-0001-9408-8901","position":5,"is_corresponding":false},{"id":363765,"name":"Kerry Kornfeld","orcid":"0000-0002-6042-5241","position":6,"is_corresponding":false},{"id":783514,"name":"Hanwenheng Liu","orcid":"0000-0001-5695-4995","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:53:12.864581Z","pmid":"40408183","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":[]}