ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex.

Journal

bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187

Informations de publication

Date de publication:
04 May 2023
Historique:
pubmed: 19 5 2023
medline: 19 5 2023
entrez: 19 5 2023
Statut: epublish

Résumé

Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region. Characterization of MDD-specific cis-regulatory elements identified ZBTB7A - a transcriptional regulator of astrocyte reactivity - as an important mediator of MDD-specific chromatin accessibility and gene expression. Genetic manipulations in mouse OFC demonstrated that astrocytic Zbtb7a is both necessary and sufficient to promote behavioral deficits, cell-type-specific transcriptional and chromatin profiles, and OFC neuronal hyperexcitability induced by chronic stress - a major risk factor for MDD. These data thus highlight a critical role for OFC astrocytes in stress vulnerability and pinpoint ZBTB7A as a key dysregulated factor in MDD that mediates maladaptive astrocytic functions driving OFC hyperexcitability.

Identifiants

DOI: 10.1101/2023.05.04.539425 PMID: 37205394 PMC: PMC10187272
pubmed: 37205394
doi: 10.1101/2023.05.04.539425
pmc: PMC10187272
pii:
doi:

Types de publication

Preprint

Langues

eng

Déclaration de conflit d'intérêts

Competing financial interests The authors declare no competing financial interests.

Auteurs

Sasha L Fulton (SL)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Jaroslav Bendl (J)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Isabel Gameiro-Ros (I)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

John F Fullard (JF)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Amni Al-Kachak (A)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ashley E Lepack (AE)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Andrew F Stewart (AF)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Sumnima Singh (S)

Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
The Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Wolfram C Poller (WC)

Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
The Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Ryan M Bastle (RM)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Mads E Hauberg (ME)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Amanda K Fakira (AK)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Min Chen (M)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Romain Durand-de Cuttoli (RD)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Flurin Cathomas (F)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Aarthi Ramakrishnan (A)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Kelly Gleason (K)

Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.

Li Shen (L)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Carol A Tamminga (CA)

Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.

Ana Milosevic (A)

Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, USA.

Scott J Russo (SJ)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Filip Swirski (F)

Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
The Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Robert D Blitzer (RD)

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.

Paul A Slesinger (PA)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Panos Roussos (P)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.
Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, USA.

Ian Maze (I)

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Classifications MeSH