Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.
Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.
Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
Davide
D
Cittaro
Developmental Psychopathology Unit, Vita-Salute San Raffaele University, Milan, Italy.
Valentina
V
Lampis
Institute of Cell Biology and Neurobiology, National Research Council/Fondazione Santa Lucia, Rome, Italy.
Alessandra
A
Luchetti
Institute of Cell Biology and Neurobiology, National Research Council/Fondazione Santa Lucia, Rome, Italy.
Roberto
R
Coccurello
Laboratory of Molecular Neuroscience, Department of Biological Chemistry, The Edmond and Lily Safra Center of Brain Science, The Hebrew University of Jerusalem, Jerusalem, Israel.|Genomnia srl, Lainate, Italy.
Alessandro
A
Guffanti
Institute of Cell Biology and Neurobiology, National Research Council/Fondazione Santa Lucia, Rome, Italy.|Genomnia srl, Lainate, Italy.
Armando
A
Felsani
Institute of Cell Biology and Neurobiology, National Research Council/Fondazione Santa Lucia, Rome, Italy.|Genomnia srl, Lainate, Italy.
Anna
A
Moles
Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
Elia
E
Stupka
Institute of Cell Biology and Neurobiology, National Research Council/Fondazione Santa Lucia, Rome, Italy.
Francesca R
FR
D' Amato
Department of Psychiatry, University Of Toronto, Toronto, Canada.|Division of Child and Youth Mental Health, Centre for Addiction and Mental Health, Toronto, Canada.
Marco
M
Battaglia
D062565:Acid Sensing Ion Channels / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001010:Anxiety, Separation / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D059647:Gene-Environment Interaction; D042421:Histone Code; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism; D051379:Mice; D016584:Panic Disorder / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D012333:RNA, Messenger; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases