{"doi":"10.1101/2025.10.31.685723","title":"lncRNA <i>3222401L13Rik</i> / <i>ENSG00000272070</i> modulates microglial inflammatory programs in association with PU.1","abstract":"Abstract Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA 3222401L13Rik as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog ENSG00000272070 . We found that 3222401L13Rik is expressed in both astrocytes and microglia and increases with age. Knockdown of 3222401L13Rik in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNFα, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog ENSG00000272070 showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, 3222401L13Rik interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, ENSG00000272070 expression was significantly reduced in postmortem Alzheimer’s disease (AD) brains, and AD-associated genes were enriched among 3222401L13Rik -regulated targets. Together, our results identify 3222401L13Rik / ENSG00000272070 as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests 3222401L13Rik as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases. Highlights 3222401L13Rik is a glia-enriched long non-coding RNA regulating microglial state Knockdown of 3222401L13Rik increases TNFα signaling The human homolog ENSG00000272070 shows reduced expression in AD brains 3222401L13Rik interacts with the AD-associated transcription factor PU.1 A conserved 3222401L13Rik –PU.1 axis modulates microglial inflammation in aging and disease","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":579720,"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":0.9472,"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":647713,"name":"M. Sadman Sakib","orcid":"0000-0002-0903-9791","position":1,"is_corresponding":false},{"id":57415,"name":"Lalit Kaurani","orcid":"0000-0002-2304-6111","position":2,"is_corresponding":false},{"id":1490651,"name":"Dennis M. Krüger","orcid":null,"position":3,"is_corresponding":false},{"id":647709,"name":"Tonatiuh Peña Centeno","orcid":"0000-0002-9329-8912","position":4,"is_corresponding":false},{"id":648797,"name":"Susanne Burkhardt","orcid":null,"position":5,"is_corresponding":false},{"id":1220246,"name":"Anna‐Lena Schütz","orcid":null,"position":6,"is_corresponding":false},{"id":806648,"name":"Deborah Kronenberg‐Versteeg","orcid":"0000-0003-0965-9998","position":7,"is_corresponding":false},{"id":545728,"name":"Ivana Delalle","orcid":"0000-0002-1873-3064","position":8,"is_corresponding":false},{"id":647723,"name":"Farahnaz Sananbenesi","orcid":"0000-0002-2123-7694","position":9,"is_corresponding":false},{"id":57417,"name":"André Fischer","orcid":"0000-0001-8546-1161","position":10,"is_corresponding":false},{"id":1221298,"name":"Ranjit Pradhan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:58:34.718602Z","pmid":"41278800","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":[]}