Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation

Pierre-Eric Lutz,Maria Aguirre,Naguib Mechawar,Jennie Yang,Tony Kwan,Carl Ernst,Gary G Chen,Alain Pacis,Ipek Yalcin,Gustavo Turecki,Adriana Redensek,Marc-Aurèle Chay,Jean-François Théroux,Tomi Pastinen,Zahia Aouabed,Elisabetta Maffioletti,Léon C Van Kempen,Jean-Christophe Grenier

doi:10.1038/s41467-021-21365-3

Abstract

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.

Highlights

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome
Among the three chromatin promoter states (Act-Prom, Wk-Prom, FlkProm, see Fig. 2e, f), mCAC was selectively enriched in WkProm, which was not observed for methylation that occurs at CG dinucleotides (mCG)
Considering that WkProm was relatively depleted in H3K27ac and H3K4me[1] compared to the two other promoter states, it is possible to hypothesize that these two histone modifications may potentially repress mCAC accumulation in brain tissue

Summary

Introduction

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. We find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. A large number of studies suggest an association between ELA and morphological and functional changes in the amygdala[3], a brain structure critically involved in emotional regulation[4] It is possible, that amygdala changes observed in individuals who experienced ELA may contribute to increased risk of psychopathology. While previous studies in psychiatry focused on the canonical form of DNA methylation that occurs at CG dinucleotides (mCG), here we investigate both CG and non-

Methods

Results

Conclusion