Differentially Methylated Plasticity Genes in the Amygdala of Young Primates Are Linked to Anxious Temperament, an at Risk Phenotype for Anxiety and Depressive Disorders
Open accessAbstract
Children with an anxious temperament (AT) are at a substantially increased risk to develop anxiety and depression. The young rhesus monkey is ideal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. Heritability, functional imaging, and gene expression studies of AT in young monkeys revealed that the central nucleus of the amygdala (Ce) is a key environmentally sensitive substrate of this at risk phenotype. Because epigenetic marks (e.g., DNA methylation) can be modulated by environmental stimuli, these data led us to hypothesize a role for DNA methylation in the development of AT. To test this hypothesis, we used reduced representation bisulfite sequencing to examine the cross-sectional genome-wide methylation levels in the Ce of 23 age-matched monkeys (1.3 ± 0.2 years) phenotyped for AT. Because AT reflects a continuous trait-like variable, we used an analytical approach that is consistent with this biology to identify genes in the Ce with methylation patterns that predict AT. Expression data from the Ce of these same monkeys were then used to find differentially methylated candidates linked to altered gene regulation. Two genes particularly relevant to the AT phenotype were BCL11A and JAG1. These transcripts have well-defined roles in neurodevelopmental processes, including neurite arborization and the regulation of neurogenesis. Together, these findings represent a critical step toward understanding the effects of early environment on the neuromolecular mechanisms that underlie the risk to develop anxiety and depressive disorders.
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Gene ontological and functional analysis of AT-associated loci and changes in gene expression included most notably GRIN1 and GRM5, which code for specific subunits of different glutamate receptors.
“Gene ontological and functional analysis of AT-associated loci and changes in gene expression, included most notably GRIN1 and GRM5, which code for specific subunits of different glutamate receptors.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
The ‘AT-associated methylation marks’ and ‘Functional AT-associated methylation marks’ sections identify GRIN1 and GRM5 among AT-associated genes and report that methylation at both correlates with gene expression. Table 1 identifies them as different types of glutamate receptor, but the paper does not describe both as receptor subunits. It also identifies BCL11A and JAG1—not GRIN1 and GRM5—as the transcripts whose expression significantly correlates with AT. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA decrease in BCL11A expression resulted in extreme anxious temperament.
“BCL11A codes for a protein involved downstream of a glutamate receptor cascade for dendritic arborization, such that a decrease in its expression resulted in extreme AT (Alisch et al., 2014).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
The Discussion reports a negative correlation between BCL11A expression and anxious-temperament severity: monkeys with extreme AT had reduced expression. It suggests that methylation-driven reduction in BCL11A expression contributes to AT, but does not establish that the decrease caused extreme AT, as “resulted in” implies. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAn increase in methylation was associated with a decrease in JAG1 expression and an increase in AT severity.
“An increase in methylation was associated with a decrease in JAG1 expression and an increase in AT severity (Alisch et al., 2014).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
The genes JAG1 and BCL11A showed methylation patterns that predicted gene expression in the AT phenotype.
“The genes JAG1 and BCL11A showed methylation patterns that predicted gene expression in the AT phenotype.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
Researchers identified almost 5500 CpG sites with AT-associated methylation, 87% of which showed a decrease in methylation levels with an increase in AT severity.
“Researchers also identified almost 5500 CpG sites with AT-associated methylation, 87% of which showed a decrease in methylation levels with an increase in AT severity.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
AT-associated methylation events were more prominent in the gene body (55%) with very little representation at the gene promoter (0-2%).
“Further analysis revealed that AT-associated methylation events were more prominent in the gene body (55%) with very little representation at the gene promoter (0–2%; Alisch et al., 2014).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
DNA methylation analysis of anxious temperament monkeys revealed genome-wide hypomethylation of CpG islands in promoter regions, particularly in TSSs (<10%), with higher methylation levels further away from the TSSs.
“DNA methylation analysis of these AT monkeys revealed genome-wide hypomethylation of CpG islands in promoter regions, particularly in TSSs (<10%), with higher methylation levels further away from the TSSs (Alisch et al., 2014).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
DMNT expression levels were not investigated in the macaque study, so the enzymes and mechanisms responsible for the reported differential DNA methylation regions in the CeA were not defined.
“DMNT expression levels were not investigated in the macaque study, so the enzymes and mechanisms responsible for the reported differential DNA methylation regions in the CeA were not defined.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Alisch et al., 2014
The DNA methylation profiling and Functional AT-associated methylation marks sections describe methylation sequencing and gene-expression analyses, but do not say whether DNMT expression was investigated. A search for DNMT, DNA methyltransferase, and the enzymes responsible for the methylation changes found no passage resolving that point or explicitly stating that the responsible mechanisms remained undefined. The copy does confirm that differential methylation was reported in the macaque central amygdala. (LLM, conf=0.67)
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- Authors
- Alisch, R. S., Chopra, P., Fox, A. S., Chen, K., White, A. T. J., Roseboom, P. H., Keles, S., & Kalin, N. H.
- Affiliations
- Emory University (US)
- University of Wisconsin–Madison (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-11-19
- Volume
- 34
- Issue
- 47
- Pages
- 15548-15556
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4236392
- OpenAlex
- W1979079340
- Cited by
- 45
- References
- 33
- Citations by year
- 2025: 3 · 2024: 4 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 10 · 2015: 5
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (P51OD011106)
- National Institute of Mental Health (MH084051, MH046729, MH081884, P50MH084051, R01MH046729, R01MH081884)
- National Human Genome Research Institute (R01HG003747)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD003352)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- anxious temperament, DNA methylation, central amygdala, rhesus monkeys, epigenetics, BCL11A, JAG1, brain development, anxiety disorders, depressive disorders, early life environment, gene expression
- MeSH terms
- Amygdala, Animals, Anxiety Disorders, Depressive Disorder, Macaca mulatta, Male, Neuronal Plasticity, Phenotype, Temperament, DNA Methylation, Gene Expression Profiling, Epigenesis, Genetic
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