{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:09:54Z","timestamp":1792786194575,"version":"4.5.0"},"posted":{"date-parts":[[2025,11,29]]},"group-title":"Neuroscience","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"NIH Common Fund","award":["1K08NS119797"],"award-info":[{"award-number":["1K08NS119797"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH Common Fund","award":["1R21HD114071"],"award-info":[{"award-number":["1R21HD114071"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH Common Fund","award":["1DP1DA063517"],"award-info":[{"award-number":["1DP1DA063517"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH Common Fund","award":["1F31NS147423"],"award-info":[{"award-number":["1F31NS147423"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH Common Fund","award":["5P50HD105354"],"award-info":[{"award-number":["5P50HD105354"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]},{"name":"United States Department of Defense","award":["HT9425-24-1-0488"],"award-info":[{"award-number":["HT9425-24-1-0488"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"crossref"}]},{"award":["Harold Amos Medical Faculty Development Award"],"award-info":[{"award-number":["Harold Amos Medical Faculty Development Award"]}],"id":[{"id":"https:\/\/ror.org\/02ymmdj85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Transient prenatal hypoxia is associated with long-term neurodevelopmental impairment without overt structural brain injury, suggesting early regulatory disruptions precede detectable pathology. Whether these disruptions represent transient stress responses or redirect developmental programs remains unknown. Here, we combined single-nucleus RNA sequencing and chromatin accessibility profiling in the late-gestation mouse cortex immediately after transient hypoxia, capturing responses across more than 140,000 nuclei. Hypoxia induced a largely conserved transcriptional stress response across cell types, whereas chromatin accessibility showed more extensive, cell type\u2013specific disruption. Developing glutamatergic neurons showed the strongest disruption of chromatin\u2013transcription coupling, with hypoxia-responsive distal regulatory regions associated with genes governing synaptic organization and neuronal excitability. Consistent with these chromatin-associated programs, juvenile offspring displayed reduced dendritic spine density and increased intrinsic excitability in cortical neurons. These results support a model in which transient hypoxia co-opts the developing epigenome\u2019s capacity to encode future transcriptional states before persistent circuit dysfunction emerges.<\/jats:p>","DOI":"10.1101\/2025.11.28.691133","type":"posted-content","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T09:30:10Z","timestamp":1764408610000},"source":"Crossref","is-referenced-by-count":0,"title":["Environmental co-option of chromatin potential links prenatal hypoxia to persistent cortical circuit dysfunction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9250-8757","authenticated-orcid":false,"given":"Ana G.","family":"Cristancho","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Division of Child Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald J.","family":"Joseph","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Division of Child Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M.","family":"Cassidy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Division of Child Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Cell and Molecular Biology PhD Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preeti S.","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan J.","family":"Gadra","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elyse C.","family":"Gadra","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donya","family":"Zarrinnegar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca N.","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3264-0902","authenticated-orcid":false,"given":"Eric D.","family":"Marsh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Division of Child Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"name":"Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026101609250910000_2025.11.28.691133v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2013.206"},{"key":"2026101609250910000_2025.11.28.691133v2.2","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/S0140-6736(18)32225-6","article-title":"Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"392","year":"2018","journal-title":"The Lancet"},{"key":"2026101609250910000_2025.11.28.691133v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2010.02.016"},{"key":"2026101609250910000_2025.11.28.691133v2.4","doi-asserted-by":"publisher","DOI":"10.1111\/apa.14821"},{"key":"2026101609250910000_2025.11.28.691133v2.5","doi-asserted-by":"publisher","DOI":"10.1159\/000499967"},{"key":"2026101609250910000_2025.11.28.691133v2.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-7687.2006.00499.x"},{"key":"2026101609250910000_2025.11.28.691133v2.7","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12727"},{"key":"2026101609250910000_2025.11.28.691133v2.8","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1001\/jamapediatrics.2019.4011","article-title":"Two-Year Neurodevelopmental Outcomes After Mild Hypoxic Ischemic Encephalopathy in the Era of Therapeutic Hypothermia","volume":"174","year":"2020","journal-title":"JAMA Pediatr"},{"key":"2026101609250910000_2025.11.28.691133v2.9","doi-asserted-by":"crossref","unstructured":"A. Riddle et al., Mild Neonatal Hypoxia Targets Synaptic Maturation, Disrupts Adult Hippocampal Learning and Memory, and Is Associated with CK2-Mediated Loss of Synaptic Calcium-Activated Potassium Channel KCNN2 Activity. J Neurosci 46, (2026).","DOI":"10.1523\/JNEUROSCI.1643-25.2026"},{"key":"2026101609250910000_2025.11.28.691133v2.10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s11689-020-09344-z","article-title":"Epigenetics modifiers: potential hub for understanding and treating neurodevelopmental disorders from hypoxic injury","volume":"12","year":"2020","journal-title":"J Neurodev Disord"},{"key":"2026101609250910000_2025.11.28.691133v2.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077859"},{"key":"2026101609250910000_2025.11.28.691133v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.devbrainres.2005.03.007"},{"key":"2026101609250910000_2025.11.28.691133v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.06.052"},{"key":"2026101609250910000_2025.11.28.691133v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.138"},{"key":"2026101609250910000_2025.11.28.691133v2.15","doi-asserted-by":"crossref","unstructured":"A. E. Trevino et al., Chromatin accessibility dynamics in a model of human forebrain development. Science 367, (2020).","DOI":"10.1126\/science.aay1645"},{"key":"2026101609250910000_2025.11.28.691133v2.16","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-10-r115"},{"key":"2026101609250910000_2025.11.28.691133v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-39919-3"},{"key":"2026101609250910000_2025.11.28.691133v2.18","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw1026"},{"key":"2026101609250910000_2025.11.28.691133v2.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau5870"},{"key":"2026101609250910000_2025.11.28.691133v2.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0810067106"},{"key":"2026101609250910000_2025.11.28.691133v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.09.056"},{"key":"2026101609250910000_2025.11.28.691133v2.22","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg3754"},{"key":"2026101609250910000_2025.11.28.691133v2.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09663-y"},{"key":"2026101609250910000_2025.11.28.691133v2.24","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1042\/BCJ20220008","article-title":"Regulation of chromatin accessibility by hypoxia and HIF","volume":"479","year":"2022","journal-title":"Biochem J"},{"key":"2026101609250910000_2025.11.28.691133v2.25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s40478-025-02062-4","article-title":"Early transcriptional responses reveal cell type-specific vulnerability and neuroprotective mechanisms in the neonatal ischemic hippocampus","volume":"13","year":"2025","journal-title":"Acta Neuropathol Commun"},{"key":"2026101609250910000_2025.11.28.691133v2.26","doi-asserted-by":"crossref","unstructured":"E. A. Lemanski et al., A Novel Non-Invasive Murine Model of Neonatal Hypoxic-Ischemic Encephalopathy Demonstrates Developmental Delay and Motor Deficits with Activation of Inflammatory Pathways in Monocytes. Cells 13, (2024).","DOI":"10.20944\/preprints202407.2364.v1"},{"key":"2026101609250910000_2025.11.28.691133v2.27","doi-asserted-by":"publisher","DOI":"10.1159\/000524045"},{"key":"2026101609250910000_2025.11.28.691133v2.28","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1038\/s41591-019-0436-0","article-title":"Human 3D cellular model of hypoxic brain injury of prematurity","volume":"25","year":"2019","journal-title":"Nat Med"},{"key":"2026101609250910000_2025.11.28.691133v2.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"2026101609250910000_2025.11.28.691133v2.30","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"2026101609250910000_2025.11.28.691133v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01282-5"},{"key":"2026101609250910000_2025.11.28.691133v2.32","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2021.04.048"},{"key":"2026101609250910000_2025.11.28.691133v2.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08079-9"},{"key":"2026101609250910000_2025.11.28.691133v2.34","unstructured":"Y. Hao et al., Integrated analysis of multimodal single-cell data. Cell, (2021)."},{"key":"2026101609250910000_2025.11.28.691133v2.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03500-8"},{"key":"2026101609250910000_2025.11.28.691133v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.039"},{"key":"2026101609250910000_2025.11.28.691133v2.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0227-y"},{"key":"2026101609250910000_2025.11.28.691133v2.38","doi-asserted-by":"crossref","unstructured":"T. Stuart , A. Srivastava , C. Lareau , R. Satija , Multimodal single-cell chromatin analysis with Signac. (2020).","DOI":"10.1101\/2020.11.09.373613"},{"key":"2026101609250910000_2025.11.28.691133v2.39","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.00858"},{"key":"2026101609250910000_2025.11.28.691133v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0591-3"},{"key":"2026101609250910000_2025.11.28.691133v2.41","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKZ1021"},{"key":"2026101609250910000_2025.11.28.691133v2.42","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ijdevneu.2018.06.012","article-title":"Hypoxia and myelination deficits in the developing brain","volume":"70","year":"2018","journal-title":"Int J Dev Neurosci"},{"key":"2026101609250910000_2025.11.28.691133v2.43","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0731-20.2020"},{"key":"2026101609250910000_2025.11.28.691133v2.44","doi-asserted-by":"crossref","unstructured":"A. D. Yucel , V. N. Gladyshev , Systemic epigenetic dysregulation as a driver of ageing and a therapeutic target. Nat Rev Mol Cell Biol, (2026).","DOI":"10.1038\/s41580-026-00958-0"},{"key":"2026101609250910000_2025.11.28.691133v2.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00790-6"},{"key":"2026101609250910000_2025.11.28.691133v2.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.05.018"},{"key":"2026101609250910000_2025.11.28.691133v2.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0079-3"},{"key":"2026101609250910000_2025.11.28.691133v2.48","doi-asserted-by":"crossref","unstructured":"X. Chen et al., Distinct behavioral traits and associated brain regions in mouse models for obsessive-compulsive disorder. Behav Brain Funct 17, 4 (2021).","DOI":"10.1186\/s12993-021-00177-x"},{"key":"2026101609250910000_2025.11.28.691133v2.49","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1001\/jamapsychiatry.2014.1582","article-title":"Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder","volume":"71","year":"2014","journal-title":"JAMA Psychiatry"},{"key":"2026101609250910000_2025.11.28.691133v2.50","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.brainres.2005.09.012","article-title":"Alterations in the dendritic morphology of prefrontal pyramidal neurons in adult rats after blockade of NMDA receptors in the postnatal period","volume":"1062","year":"2005","journal-title":"Brain Res"},{"key":"2026101609250910000_2025.11.28.691133v2.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2017.06.035"},{"key":"2026101609250910000_2025.11.28.691133v2.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01476-y"},{"key":"2026101609250910000_2025.11.28.691133v2.53","doi-asserted-by":"crossref","unstructured":"S. Sakai et al., In vivo transition in chromatin accessibility during differentiation of deep-layer excitatory neurons in the neocortex. Development 152, (2025).","DOI":"10.1242\/dev.204564"},{"key":"2026101609250910000_2025.11.28.691133v2.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2825-4"},{"key":"2026101609250910000_2025.11.28.691133v2.55","doi-asserted-by":"crossref","first-page":"867120","DOI":"10.3389\/fnins.2022.867120","article-title":"Maternal Hypoxia Increases the Excitability of Neurons in the Entorhinal Cortex and Dorsal Hippocampus of Rat Offspring","volume":"16","year":"2022","journal-title":"Front Neurosci"},{"key":"2026101609250910000_2025.11.28.691133v2.56","doi-asserted-by":"crossref","unstructured":"E. C. Gadra , A. G. Cristancho , A Simplified Paradigm of Late Gestation Transient Prenatal Hypoxia to Investigate Functional and Structural Outcomes from a Developmental Hypoxic Insult. Bio Protoc 12, (2022).","DOI":"10.21769\/BioProtoc.4519"},{"key":"2026101609250910000_2025.11.28.691133v2.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"2026101609250910000_2025.11.28.691133v2.58","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2021.04.021"},{"key":"2026101609250910000_2025.11.28.691133v2.59","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"2026101609250910000_2025.11.28.691133v2.60","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"2026101609250910000_2025.11.28.691133v2.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0414-6"},{"key":"2026101609250910000_2025.11.28.691133v2.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2010.03.001"},{"key":"2026101609250910000_2025.11.28.691133v2.63","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"2026101609250910000_2025.11.28.691133v2.64","doi-asserted-by":"crossref","unstructured":"H. Roux de Bezieux, K. Van den Berge, K. Street, S. Dudoit, Trajectory inference across multiple conditions with condiments. Nat Commun 15, 833 (2024).","DOI":"10.1038\/s41467-024-44823-0"},{"key":"2026101609250910000_2025.11.28.691133v2.65","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4772-0"},{"key":"2026101609250910000_2025.11.28.691133v2.66","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107591"},{"key":"2026101609250910000_2025.11.28.691133v2.67","doi-asserted-by":"crossref","first-page":"101999","DOI":"10.1016\/j.isci.2020.101999","article-title":"Postnatal Arx transcriptional activity regulates functional properties of PV interneurons","volume":"24","year":"2021","journal-title":"iScience"},{"key":"2026101609250910000_2025.11.28.691133v2.68","doi-asserted-by":"publisher","DOI":"10.1113\/JP274258"},{"key":"2026101609250910000_2025.11.28.691133v2.69","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41398-018-0132-8","article-title":"Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia","volume":"8","year":"2018","journal-title":"Transl Psychiatry"},{"key":"2026101609250910000_2025.11.28.691133v2.70","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.cels.2018.10.007","article-title":"BioJupies: Automated Generation of Interactive Notebooks for RNA-Seq Data Analysis in the Cloud","volume":"7","year":"2018","journal-title":"Cell Syst"},{"key":"2026101609250910000_2025.11.28.691133v2.71","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.28.691133","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:25:24Z","timestamp":1792167924000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.28.691133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,29]]},"references-count":71,"URL":"https:\/\/doi.org\/10.1101\/2025.11.28.691133","relation":{},"subject":[],"published":{"date-parts":[[2025,11,29]]},"subtype":"preprint"}}