{"doi":"10.1101/2025.09.24.678226","title":"Nuclear Argonaute HRDE-1 Maintains Chromatin-Independent Transcriptional Silencing through a Transgenerational Small RNA Feedback Loop","abstract":"Abstract Epigenetic inheritance of transcriptional silencing is traditionally attributed to chromatin-based mechanisms in which Argonaute–small RNA complexes recruit histone-modifying enzymes. Here we show that, in Caenorhabditis elegans , the nuclear Argonaute HRDE-1 maintains germline transcriptional repression independently of canonical heterochromatin marks. Using inducible, germline-specific HRDE-1 depletion combined with nuclear sorting, CUT&Tag, and nascent transcription profiling, we identified endogenous genes that become transcriptionally activated upon loss of HRDE-1 despite retaining H3K9me3 and H3K23me3. HRDE-1 directly restrains RNA polymerase II (Pol II) while simultaneously promoting polyUG-dependent amplification of antisense 22G-RNAs in perinuclear condensates, thereby coupling nuclear transcriptional repression to small RNA biogenesis. HRDE-1 loss causes progressive erosion of 22G-RNAs and delays silencing re-establishment, revealing a transgenerational feedback loop in which small RNAs, and not chromatin modifications, constitute the primary heritable signal. These findings redefine nuclear Argonautes as active drivers of RNA-based epigenetic inheritance and broaden our understanding of how small RNA pathways maintain transcriptional silencing across generations.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556780,"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":2,"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":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1456448,"name":"Almira Chervova","orcid":"0000-0002-8951-1127","position":1,"is_corresponding":false},{"id":557138,"name":"Loan Bourdon","orcid":"0000-0001-7502-753X","position":2,"is_corresponding":false},{"id":1456870,"name":"Jagannath Jayaraj","orcid":null,"position":3,"is_corresponding":false},{"id":646477,"name":"Ana Karina Morao","orcid":"0000-0003-2194-8071","position":4,"is_corresponding":false},{"id":1456449,"name":"Olivier Ulrich Feudjio","orcid":"0000-0001-9621-836X","position":5,"is_corresponding":false},{"id":1456871,"name":"Sofija Illic","orcid":null,"position":6,"is_corresponding":false},{"id":1456872,"name":"S. A. Capurso","orcid":null,"position":7,"is_corresponding":false},{"id":272214,"name":"Piergiuseppe Quarato","orcid":"0000-0003-3839-3383","position":8,"is_corresponding":false},{"id":1456873,"name":"Julie Ovieve","orcid":null,"position":9,"is_corresponding":false},{"id":272215,"name":"Germano Cecere","orcid":"0000-0001-5912-3417","position":10,"is_corresponding":false},{"id":1456447,"name":"Arantxa M. L. Rojas","orcid":"0000-0003-4316-4518","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"41377513","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":[]}