DNA methylation, the early-life social environment and behavioral disorders

Abstract

One of the outstanding questions in behavioral disorders is untangling the complex relationship between nurture and nature. Although epidemiological data provide evidence that there is an interaction between genetics (nature) and the social and physical environments (nurture) in a spectrum of behavioral disorders, the main open question remains the mechanism. Emerging data support the hypothesis that DNA methylation, a covalent modification of the DNA molecule that is a component of its chemical structure, serves as an interface between the dynamic environment and the fixed genome. We propose that modulation of DNA methylation in response to environmental cues early in life serves as a mechanism of life-long genome adaptation. Under certain contexts, this adaptation can turn maladaptive resulting in behavioral disorders. This hypothesis has important implications on understanding, predicting, preventing, and treating behavioral disorders including autism that will be discussed.

Fig. 1

DNA methylation reactions. DNA methyltransferases transfer methyl groups (CH₃) from the methyl donor S-adenosyl-l-methionine to cytosines in DNA. Two kinds of DNA methylation reactions are shown; de novo methyltransferases (DNMT3a and DNMT3b) add new methyl groups to cytosines in DNA, maintenance DNA methyltransferase (DNMT1) copies the DNA methylation pattern from the template strand following DNA replication. Passive demethylation: if DNMT1 is absent during DNA replication, the DNA will be copied without being methylated and will be thus “passively” demethylated. DNA could be actively demethylated by demethylases that remove the methyl groups from DNA in the absence of DNA replication (see Fig. 2)

Fig. 2

Mechanisms of active DNA demethylation. Several demethylation reactions were suggested. Direct demethylation by a demethylase enzyme (dMTase; MBD2 is a putative candidate) could release a methyl moiety (CH₃) in the form of either methanol or formaldehyde. Alternatively, the methyl cytosine ring could be modified by either deamination catalyzed for example by AID or by the DNA methyltransferases (DNMT) which were shown to catalyze deamination of 5-methylcytidine in the absence of SAM or hydroxylation of the methyl moiety catalyzed by TET1. The modified base is then excised and repaired. Alternatively, the bond between the sugar and the base is cleaved (by glycosylases such as MBD4 or 5-methylcytosine glycosylase 5-MCDG) followed by repair. Repair proteins shown to be associated with demethylation were GADD45(a and b)

Fig. 3

The early-life environment modulates the DNA methylation equilibrium; reversibility of DNA methylation. The DNA methylation equilibrium is laid down during embryogenesis by innate developmental programs. Increased methylation of promoters is associated with a hypoacetylated and poorly transcribed gene (right) and hypomethylated promoter is hyperacetylated and highly transcribed (left). A balance of DNA methylation and demethylation activities dynamically maintains this pattern and is attuned to signals from the early environment that can modulate the pattern through activation of signaling pathways that facilitate either increased demethylation or increased methylation. Two examples were previously reported; maternal licking and grooming increases serotonin firing increasing cAMP and activation of protein kinase A, which in turn activates NGFIA facilitating demethylation and histone acetylation of the GR exon 1₇ promoter. Early-life stress triggers activation of CAMKII kinase resulting in phosphorylation of MeCP2 (P). Phosphorylated MeCP2 facilitates demethylation and increased transcription of genes such as AVP. The DNA methylation balance set by early-life environment could be reversed during adulthood using epigenetic modifiers such as the histone deacetylase inhibitor TSA or methionine the precursor of the methyl donor SAM resulting in an epigenetic and behavioral reversal of the phenotype defined by maternal care. (AC histone acetylation, CH₃ DNA methylation)