COMPASS-mediated epigenetic regulation of transcription accelerates forgetting with age

COMPASS-mediated epigenetic regulation of transcription accelerates forgetting with age | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article COMPASS-mediated epigenetic regulation of transcription accelerates forgetting with age Titas Sengupta, Rachel Kaletsky, Katherine Morillo, Shiyi Zhou, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9395284/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The molecular regulation of forgetting and its acceleration with age are not understood. Here we discovered that active gene transcription, rather than solely mRNA translation, is required for forgetting. We found that the subunits of SET1/COMPASS, a conserved histone methyltransferase complex associated with active transcription, are upregulated in aged C. elegans neurons, mirroring their age-related increase in mammalian brain regions governing memory. Reduction of SET1/COMPASS components blocks forgetting in both young and old animals. Optogenetic manipulation, degron-mediated conditional knockdown, pharmacological and genetic inhibition, neuronal RNA-Seq, and neuronal chromatin profiling reveal that SET1/COMPASS promotes activity-dependent de novo transcription in an olfactory sensory neuron that erases the associative memory trace in downstream neurons via neuropeptide signaling, resulting in forgetting. Increased SET1/COMPASS-dependent chromatin accessibility at these loci primes transcription, accelerating forgetting with age. Rescue with human SET1A and an inhibitor of human COMPASS underscore the conservation of this pathway from worms to humans. Our results identify SET1/COMPASS-mediated de novo gene transcription as a mechanism of forgetting,​​ implicating increased expression of COMPASS components as a conserved driver of cognitive decline with age. Biological sciences/Neuroscience/Cognitive ageing Biological sciences/Neuroscience/Epigenetics in the nervous system Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SuppTable3genesbyTFmotif.xlsx Table S3 Genes by TF motif SuppTable4DifferentiallyaccessibleregionsWT.xlsx Table S4 ATACseq WT SuppTable2AWCRNAseqDifferentiallyexpressedgenes.xlsx Table S2 AWC Diff exp SuppTable6Sourcedata.xlsx Table S6 Source data SuppTable5Differentiallyaccessibleregionsmutant.xlsx Table S5 ATACseq set2 SuppTable1WTAWC0hrranked.xlsx Table S1 AWC 0hr Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9395284","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":623923132,"identity":"74679fb4-3b0f-4434-898b-2909eaaa37c0","order_by":0,"name":"Titas Sengupta","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Titas","middleName":"","lastName":"Sengupta","suffix":""},{"id":623923133,"identity":"2967bf13-1e0d-4b68-85d3-25468c703ab2","order_by":1,"name":"Rachel Kaletsky","email":"","orcid":"https://orcid.org/0000-0002-7176-9154","institution":"Princeton 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Here we discovered that active gene transcription, rather than solely mRNA translation, is required for forgetting. We found that the subunits of SET1/COMPASS, a conserved histone methyltransferase complex associated with active transcription, are upregulated in aged C. elegans neurons, mirroring their age-related increase in mammalian brain regions governing memory. Reduction of SET1/COMPASS components blocks forgetting in both young and old animals. Optogenetic manipulation, degron-mediated conditional knockdown, pharmacological and genetic inhibition, neuronal RNA-Seq, and neuronal chromatin profiling reveal that SET1/COMPASS promotes activity-dependent de novo transcription in an olfactory sensory neuron that erases the associative memory trace in downstream neurons via neuropeptide signaling, resulting in forgetting. Increased SET1/COMPASS-dependent chromatin accessibility at these loci primes transcription, accelerating forgetting with age. 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