bioRxiv : the preprint server for biology最新文献

{"title":"Spatiotemporal AI modeling of gene regulation and variant effects in the developing human brain.","authors":"Yun Hao, Christopher Y Park, Chandra T Theesfeld, Olga G Troyanskaya","doi":"10.64898/2026.10.09.757610","DOIUrl":"https://doi.org/10.64898/2026.10.09.757610","url":null,"abstract":"<p><p>Understanding how genetic variation shapes gene regulation in the developing human brain remains a central challenge in neuroscience, particularly in transient cell types and developmental stages where data are limited. We present Seal, an interpretable AI transfer learning framework for genome-based modeling of gene expression and variant effects with spatiotemporal resolution across 26 brain regions, 30 cell types, and seven developmental stages. Seal predictions enable characterization of both germline and somatic brain variants, and provide mechanistic interpretation by linking sequence variants to transcriptional regulators in spatiotemporal context. Applying Seal to genome-wide association studies, we identify cell types and developmental windows relevant to neuropsychiatric disease risk, revealing shared and distinct regulatory architectures across six neuropsychiatric conditions that align with clinical trajectories. In the Simons Simplex Collection autism cohort whole genome data, Seal uncovers a significant burden of de novo regulatory variants in transient fetal excitatory neurons, revealing a cell-type and developmentally specific regulatory burden. By connecting genetic variation to spatiotemporal regulatory programs, Seal offers a general framework for uncovering mechanisms of human brain development and disease.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149280196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"A human <i>CHRNA6</i> 3' UTR variant alters the molecular environment and microRNA engagement of the adolescent VTA without changing <i>Chrna6</i> transcript abundance\".","authors":"Yasamin Hajy Heydary, Emily M Castro, Kaylie S Gurholt, Nikki Le, Frances M Leslie, Shahrdad Lotfipour","doi":"10.64898/2026.10.09.758057","DOIUrl":"https://doi.org/10.64898/2026.10.09.758057","url":null,"abstract":"<p><p>A single nucleotide polymorphism (rs2304297) in the 3' untranslated region (UTR) of <i>CHRNA6</i> , encoding the α6 nicotinic acetylcholine receptor subunit, is associated with adolescent smoking behavior. Humanized rats carrying the \"C\" or \"G\" allele show sex- and genotype-dependent responses to adolescent nicotine, yet the variant does not alter the protein sequence and the mechanism has remained unknown. We examined the molecular consequences of rs2304297 <i>in vivo</i> in the adolescent ventral tegmental area (VTA). <i>Chrna6</i> transcript abundance did not differ by genotype, nor did transcript stability or polyadenylation site selection. The variant was instead associated with a transcriptional signature spanning myelin maintenance ( <i>Enpp6</i> ), lipid metabolism ( <i>Retsat</i> ), and genomic repair ( <i>Polq</i> ), and with elevated basal lipid peroxidation in α6 ^GG animals. Computational folding predicted greater conformational flexibility of the \"G\" allele, and spatial colocalization of <i>Chrna6</i> with miRNA-365-5p was reduced in α6 ^GG animals of both sexes. Coordinated expression of the two transcripts, however, followed a sex-by-genotype pattern, absent in α6 ^CC females and α6 ^GG males. These same groups showed elevated tyrosine hydroxylase expression and dopaminergic neuron number, and expansion of the <i>Chrna6</i> co-expression network following nicotine. We propose that rs2304297 acts through two distinct layers: genotype determines spatial engagement of miRNA-365-5p with the transcript, while sex determines whether that engagement produces functional regulation. These findings identify a post-transcriptional mechanism for a non-coding nicotine addiction risk variant and demonstrate that its molecular effect can be uniform while its consequences are not.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A large, comprehensive labeled MRI dataset of the human lateral ventricle choroid plexus.","authors":"Ling-Yu Huang, Victor Zeng, Nicolas Raymond, Brendan Stiltner, Willa Molho, Yuan Cao, Deepthi Bannai, Daphne Ying, Emma Oss, Daman P Dhunna, Prachi Patel, Alexa Adesokan, Morgan Hricay, Victoria Lyons, Noah Tolentino, Matcheri S Keshavan, Peter Fried, Mohammad Jammoul, David Kuegler, Santiago Estrada, Martin Reuter, Paulo Lizano","doi":"10.64898/2026.10.08.757728","DOIUrl":"https://doi.org/10.64898/2026.10.08.757728","url":null,"abstract":"<p><p>The choroid plexus (ChP) is a highly vascularized structure located in the brain ventricles that plays important roles in multiple central nervous system functions. ChP enlargement has been implicated in many neuropsychiatric conditions such as multiple sclerosis, depression, schizophrenia, and Alzheimer's disease. However, limitation in the accuracy of the current segmentation tools highlight the need for more reliable methods to quantify ChP volume in healthy and clinical human populations. The shape and size of the ChP vary drastically from person to person, and currently there are no large ChP datasets which allow comprehensive training of segmentation models. Here we introduce DataPlex, a collection of 700 structural MRI brain images where the lateral ventricle ChP has been manually labeled and checked by expert human raters. DataPlex is balanced and representative across a wide range of scanning parameters, demographics, and clinical profiles, and subject-level information will be available for each labeled image. DataPlex will be open source to support the creation of reliable segmentation tools for the human lateral ventricle ChP.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perturb-Seqr: Signature Search Engine Integrating Connectivity Mapping Resources.","authors":"Lily D Taub, John Gardner, Ido Diamant, Daniel J B Clarke, Avi Ma'ayan","doi":"10.64898/2026.10.06.757137","DOIUrl":"https://doi.org/10.64898/2026.10.06.757137","url":null,"abstract":"<p><p>High-throughput transcriptomics can be used to develop Connectivity Mapping resources for identifying potential reversers and mimickers of disease signatures for drug and target discovery. Recently, several new Connectivity Mapping datasets have emerged, but no efforts were made so far to evaluate and integrate them. Motivated by this opportunity, we have developed Perturb-Seqr, a comprehensive Connectivity Mapping search engine that integrates nine small molecule transcriptomics Connectivity Maps and seven single gene perturbation followed by expression Connectivity Maps. Specifically, Perturb-Seqr contains processed data from LINCS (L1000), Tahoe-100M, Novartis Institute for Biomedical Research (DRUG-seq), the original CMap (cDNA microarrays), Ginkgo Bioworks (DRUG-seq), SciPlex (scRNA-seq), DeepCover MoA (PISA proteomics), Perturb Atlas (RNA-seq), Replogle et al. (Perturb-seq), CREEDS (cDNA microarrays), CM4AI (Perturb-seq), and RummaGEO (RNA-seq). To serve these Connectivity Maps in one unifying search engine, we converted the expression signatures from these resources into 450,271 gene sets of up- and down-regulated genes measuring the effects of 9,856 unique drug and 17,643 unique gene perturbations, targeting 917 cell lines and cell types. We demonstrate how Perturb-Seqr, and the gene sets it serves, can be used to identify targets for drugs and drugs for targets, uncover new pathways, and identify potential side effects for preclinical compounds. Overall, Perturb-Seqr is a comprehensive up-to-date Connectivity Mapping search engine and database, enabling the discovery of new drugs and targets. Perturb-Seqr is accessible from: https://perturbseqr.maayanlab.cloud/ .</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impacts of different <i>SETD1A</i> mutations and genetic backgrounds on human induced pluripotent stem cell-derived hippocampal neurons.","authors":"Yan Hong, Ting Zhao, Qian Yang, Hanwen Zhang, Xueting Ma, Xiao Su, Jiayi Liu, Siwei Zhang, Karla Mendez-Maldonado, Yi Zhou, Jizhong Zou, Anat Kreimer, Akira Sawa, Kimberly M Christian, Zhiping P Pang, Jubao Duan, Hongjun Song, Guo-Li Ming","doi":"10.64898/2026.10.07.756381","DOIUrl":"https://doi.org/10.64898/2026.10.07.756381","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (hiPSCs) provide a translational platform to interrogate the impact of genetic risk factors for various disorders on human biology. It has been a common practice to engineer premature stop codons to model predicted loss-of-function mutations using isogenic hiPSCs, yet effects of mutation position for the same gene and genetic background have been rarely tested systematically and at multiple levels for comparison to those of patient-specific mutations. Ultra-rare, heterozygous, and predicted loss-of-function mutations in the <i>SETD1A</i> gene, which encodes a H3K4 methyltransferase, are highly penetrant genetic risk factors for schizophrenia. Here, we generated a large panel of isogenic heterozygous <i>SETD1A</i> mutant hiPSC lines, including premature stop-codon mutations in one early exon and one late exon in five genetic backgrounds and two patient-specific mutations, to gain insight into molecular, cellular, and functional changes in a disease-relevant and highly pure population of human hippocampal dentate granule cell-like neurons. Our multi-level analyses showed that different <i>SETD1A</i> mutations lead to divergent molecular and cellular phenotypes related to synapses, but convergent neuronal network deficits, while the genetic background influences gene expression with no substantial effects at cellular and network levels. Mechanistic analysis confirmed the early exon patient mutation as loss-of-function, but revealed that the predicted loss-of-function patient mutation in the late exon is likely gain-of-function. Consequently, while all mutations decreased global H3K4me3 levels, deficits were only partially rescued by inhibiting H3K4 demethylase LSD1 for early exon mutations, but not for late exon mutations. Together, these results suggest that highly penetrant mutations can lead to similar cellular and functional phenotypes across different genetic backgrounds, whereas different premature stop-codon mutations could have contrasting impacts due to distinct mechanisms. Our findings have practical implications for applying genome-editing in hiPSCs to model disorders, highlight the value of modeling patient-specific mutations and testing multiple mutations, and suggest the need for tailored mutation-dependent therapeutic strategies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional perturbation effects remain structured beyond the leading global trend.","authors":"Qiyuan Liu, Qirui Zhang, Yilong Chen, Jinhong Du, Siming Zhao, Jingshu Wang","doi":"10.64898/2026.10.05.756839","DOIUrl":"https://doi.org/10.64898/2026.10.05.756839","url":null,"abstract":"<p><p>Prior work has described a global transcriptional response to gene perturbation, with many perturbations moving cells along a common direction. We find that perturbations contribute differently to this leading global trend and that substantial organization remains beyond it, including transferable perturbation-specific effects across datasets and a common hierarchy of responsive genes across perturbations. These patterns make simple strategies surprisingly competitive even in predicting effects beyond the leading global component.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149280199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IsoGraph resolves coordinated transcript choice and gene abundance in the aging human brain.","authors":"Alexis Bennett, Elisa Kain Johnson, Kynon J M Benjamin","doi":"10.64898/2026.10.04.756439","DOIUrl":"https://doi.org/10.64898/2026.10.04.756439","url":null,"abstract":"<p><p>Relative transcript usage can change without a corresponding change in total gene expression, but resolving coordinated transcript choice across genes while separating it from abundance remains challenging. We present IsoGraph, a gene-centered framework that represents isoform usage and abundance as paired network channels, identifies gene modules, and quantifies their channel-specific contributions. In synthetic benchmarks, IsoGraph preferentially recovered network structure when coordinated transcript usage carried the planted signal, whereas abundance-based representations were more informative in abundance-dominated and RNA-degradation settings. Applied to BrainSEQ and GTEx adult brain transcriptomes, IsoGraph identified age-associated transcript-usage signals that persisted after conditioning on gene abundance and, in a region-dependent manner, after adjustment for estimated cellular composition. Modules were stable across donor subsets, and frozen module axes retained age associations across cohorts even when exact gene partitions differed. IsoGraph module context captured predictive information about held-out differential transcript usage beyond gene-wise evidence and conventional co-expression. Convergent evidence from structural annotation, short-read junction usage, independent long-read sequencing, and within-donor allelic analyses supported constituent transcript events. Disease colocalization further prioritized candidate isoform events at neurological and psychiatric disease loci, including an alternative terminal-exon event at <i>PRDM2</i> associated with amyotrophic lateral sclerosis. Together, these results establish coordinated transcript usage as a reproducible component of transcriptomic organization and provide a framework for resolving its contribution alongside gene abundance and for tracing network-level signals to candidate transcript events.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Onset of Breathing at Birth Switches Off Regenerative Capacity.","authors":"Xuan Song, Xinyi Cai, Shane V Hegarty, Davide Speri, Masahiro Yasuda, Ryan J Donahue, Joanna Stanicka, Ting Yan, Susu Mao, Sarah Yang, Jiawen Chen, Junjie Zhu, James K Kiraly, Cheng-Hao Chien, Evgenii Kegeles, Daniel Feng, Kevin C Stieger, Zhiyun Yang, Yiming Zhang, Gary Yellen, Hisashi Umemori, Philip R Williams, Zhigang He","doi":"10.64898/2026.10.03.756425","DOIUrl":"https://doi.org/10.64898/2026.10.03.756425","url":null,"abstract":"<p><p>Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood1-3, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential4-11, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO₂ exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO₂ exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK)12-14, which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO₂ inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO₂ inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO₂/pH signaling shapes the regenerative capacity across life and pointing to a potential CO₂-based strategy for promoting tissue regeneration.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149280057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrosis burden and spatial pattern affect left atrial appendage stasis in multi-beat multi-physics simulations.","authors":"Yvonne Stöcker, Christoph M Augustin, Manuel Guerrero-Hurtado, Oscar Flores, Alejandro Gonzalo, Åshild Telle, Patrick Boyle, Nazem Akoum, Juan C Del Alamo, Manuel García-Villalba","doi":"10.64898/2026.09.26.754330","DOIUrl":"10.64898/2026.09.26.754330","url":null,"abstract":"<p><p><b>Purpose:</b> Atrial fibrosis is associated with thromboembolic risk in atrial fibrillation, but it remains unclear how fibrosis-related contractile impairment alters blood transport in the left atrium (LA) and left atrial appendage (LAA). Prior multi-physics simulations coupling electromechanical (EM) and computational fluid dynamics (CFD) models showed that fibrosis impairs LA function and flow, but were limited to booster-only contraction and could not separate the effects of fibrosis burden from its spatial distribution. Here, we examined how fibrosis burden and spatial pattern independently relate to long-term LA and LAA hemodynamics in full-cycle, multi-beat simulations on a common LA anatomy. <b>Methods:</b> Three fibrosis patterns derived from late gadolinium enhancement MRI were applied globally to a common LA anatomy at matched burdens of 15.6% and 31.2%, yielding six global-fibrosis cases and a non-fibrotic reference. Two patterns were also confined to the LAA at local burdens of 10%, 25%, and 50%, yielding six LAA-fibrosis cases. A 3D EM model of the LA anatomy coupled to a 0D circulatory model resolved the reservoir, conduit, and booster phases, and the EM-derived wall motion drove subsequent multi-beat CFD simulations. Region-specific emptying fraction (EF), non-dimensional kinetic energy (KE), and the 90th percentile of blood residence time (T _R ) were evaluated in the LA and LAA. <b>Results:</b> Left ventricular stroke volume remained nearly constant across cases, whereas increasing global fibrosis burden progressively reduced LA and LAA EF (LA: 36% to 30-31%; LAA: 44% to 28-38%), lowered both active and passive LA EF, and monotonically increased LA T _R across all patterns. Non-dimensional LA KE showed an approximately quadratic association with LA EF across patterns, whereas LAA KE was more scattered but still increased with LAA EF. In contrast, the 90th percentile of LAA T _R did not increase monotonically with decreasing LAA EF for one pattern. When fibrosis was confined to the LAA, non-dimensional LAA KE collapsed onto a single relationship with LAA EF for both patterns, whereas LAA T _R followed distinct, non-monotonic trends. <b>Conclusions</b> : Fibrosis burden, through its association with functional impairment, predominantly governed whole-LA hemodynamics, whereas LAA stasis additionally depended on the spatial distribution of fibrosis. In the LAA-fibrosis cases, LAA EF was a robust descriptor of chamber-averaged KE regardless of fibrosis pattern, but did not fully explain LAA residence time. These findings support evaluating imaging-derived fibrosis pattern, in addition to fibrosis burden and functional metrics, as a potential determinant of LAA transport and stasis. Its incremental value for thrombogenic-risk assessment requires prospective clinical validation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3 inhibition attenuates the macrophage type I interferon response.","authors":"Edward M C Courvan, Cody J S Hecht, Frederick Longshore-Neate, Luisa Macedo de Vasconcelos, Roy Parker","doi":"10.64898/2026.08.14.744930","DOIUrl":"10.64898/2026.08.14.744930","url":null,"abstract":"<p><p>Macrophages coordinate inflammatory responses to changing tissue conditions and invasion by pathogens. Post-transcriptional regulation of the transcriptome via RNA decay is a crucial element of these responses. N⁶-methyladenosine (m⁶A) deposition on mRNA constitutes one such post-transcriptional pathway, where the methyltransferase METTL3 and the oxygen dependent eraser ALKBH5 regulate m⁶A levels. We used TimeLapse-seq to measure transcriptome-wide abundance, decay, and transcription in THP1 macrophages comparing the effects of the METTL3 inhibitor STM2457 and hypoxia. We found no evidence that hypoxia and STM2457 affect RNA decay by a shared mechanism but discovered that METTL3 inhibition transcriptionally downregulates the interferon response through STAT1. Consequently, STM2457 treatment makes both THP1 and peripheral blood macrophages are more permissive to infection by the human coronavirus OC43. We conclude that macrophages depend on METTL3 activity to support the interferon response, an effect that appears distinct to macrophages and suggests METTL3 inhibitors could control macrophage driven inflammation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13691975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}