Conserved DNA Methylation Signatures in Early Maternal Separation and in Twins Discordant for CO2 Sensitivity

Francesca Giannese,Simona Scaini,Gun Peggy Knudsen,Valentina Lampis,Alessandra Luchetti,Dejan Lazarevic,Marco Battaglia,Claudio Zanettini,Giulia Barbiera,Francesca R D’Amato,Davide Cittaro

doi:10.1038/s41598-018-20457-3

Abstract

Respiratory and emotional responses to blood-acidifying inhalation of CO2 are markers of some human anxiety disorders, and can be enhanced by repeatedly cross-fostering (RCF) mouse pups from their biological mother to unrelated lactating females. Yet, these dynamics remain poorly understood. We show RCF-associated intergenerational transmission of CO2 sensitivity in normally-reared mice descending from RCF-exposed females, and describe the accompanying alterations in brain DNA methylation patterns. These epigenetic signatures were compared to DNA methylation profiles of monozygotic twins discordant for emotional reactivity to a CO2 challenge. Altered methylation was consistently associated with repeated elements and transcriptional regulatory regions among RCF-exposed animals, their normally-reared offspring, and humans with CO2 hypersensitivity. In both species, regions bearing differential methylation were associated with neurodevelopment, circulation, and response to pH acidification processes, and notably included the ASIC2 gene. Our data show that CO2 hypersensitivity is associated with specific methylation clusters and genes that subserve chemoreception and anxiety. The methylation status of genes implicated in acid-sensing functions can inform etiological and therapeutic research in this field.

Highlights

Sensitivity to CO2 is enhanced in humans with panic disorder (PD), amongst whom exaggerated respiratory and emotional reactivity to blood-acidifying CO2-enriched air mixtures[4,5], increased propensity to asthma and finely altered ventilator physiology[6], and sudden increase of CO2 partial pressure preceding spontaneous panic attacks[7] are well documented
A major impetus to the present study was provided by evidence that, to human CO2 hypersensitivity[17], repeatedly cross-fostering (RCF)-induced CO2 hypersensitivity is sensitive to GxE mechanisms[20], as indicated by the enhanced heritability of tidal volume increment during 6%CO2 breathing among RCF animals[20]
We investigated the DNA methylation profiles of animals exposed to the RCF paradigm, and of human monozygotic twin pairs discordant for CO2 hypersensitivity (MZD), together with the patterns of inheritance of such regions, and the RCF-associated intergenerational transmission of CO2 hypersensitivity

Summary

Introduction

Sensitivity to CO2 is enhanced in humans with panic disorder (PD), amongst whom exaggerated respiratory and emotional reactivity to blood-acidifying CO2-enriched air mixtures[4,5], increased propensity to asthma and finely altered ventilator physiology[6], and sudden increase of CO2 partial pressure preceding spontaneous panic attacks[7] are well documented. Childhood parental loss (including separation from parents, divorce, death) adds significantly to this covariation[14], and early-life adversities heighten individual responsiveness to CO2 via gene-by-environment interaction mechanism (GXE)[17]. Independent groups transferred this knowledge to the animal laboratory, and responses to CO2 and brain acidification became translational tools to investigate PD by proxies in animals[18,19,20,21,22]. A major impetus to the present study was provided by evidence that, to human CO2 hypersensitivity[17], RCF-induced CO2 hypersensitivity is sensitive to GxE mechanisms[20], as indicated by the enhanced heritability of tidal volume increment during 6%CO2 breathing among RCF animals[20]. Altered chromatin structure and enhanced expression of the Acid Sensing Ion Channels[1]

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Discussion

Conclusion