Figures & data
DNA methylation, which utilizes the universal methyl donor SAM, is catalyzed by members of the DNMT family of proteins (DNMT 1, 3a and 3b). 5mC is a repressive chromatin mark that negatively correlates with gene expression. The demethylation of DNA, which re-activates transcription, occurs through several steps that involve the hydroxylation of the methylated cytosine. DNA hydroxymethylation, the first step in this cascade, is catalyzed by members of the TET (TETs 1–3) family of Fe(II)/α-ketoglutarate-dependent dioxygenases. These enzymes further oxidize the hydroxymethyl group to form 5fC and 5caC. Both 5fC and 5caC can be excised by TDG generating an abasic site which is subsequently replaced by BER enzymes regenerating the unmodified C. The intermediates in DNA demethylation (5hmC, 5fC and 5caC) accumulate to different extents in cells indicating that each epigenetic DNA mark is stable and likely serves a distinct function. This is thought to occur by the interaction of each modified base with a variety of DNA readers [Citation86,Citation87]. For example, unmodified cytosines (5C) are recognized and bound by proteins such as DNMT1 and TET1 that contain a -CXXC- motif in their zinc finger DNA-binding domain [Citation42]. Methyl-binding domain proteins, like MeCP2 and other MBDs, bind to 5mC.
BER: Base excision repair; SAM: S-adenosylmethionine.
![Figure 1. DNA demethylation pathway.DNA methylation, which utilizes the universal methyl donor SAM, is catalyzed by members of the DNMT family of proteins (DNMT 1, 3a and 3b). 5mC is a repressive chromatin mark that negatively correlates with gene expression. The demethylation of DNA, which re-activates transcription, occurs through several steps that involve the hydroxylation of the methylated cytosine. DNA hydroxymethylation, the first step in this cascade, is catalyzed by members of the TET (TETs 1–3) family of Fe(II)/α-ketoglutarate-dependent dioxygenases. These enzymes further oxidize the hydroxymethyl group to form 5fC and 5caC. Both 5fC and 5caC can be excised by TDG generating an abasic site which is subsequently replaced by BER enzymes regenerating the unmodified C. The intermediates in DNA demethylation (5hmC, 5fC and 5caC) accumulate to different extents in cells indicating that each epigenetic DNA mark is stable and likely serves a distinct function. This is thought to occur by the interaction of each modified base with a variety of DNA readers [Citation86,Citation87]. For example, unmodified cytosines (5C) are recognized and bound by proteins such as DNMT1 and TET1 that contain a -CXXC- motif in their zinc finger DNA-binding domain [Citation42]. Methyl-binding domain proteins, like MeCP2 and other MBDs, bind to 5mC.BER: Base excision repair; SAM: S-adenosylmethionine.](/cms/asset/132bb7af-12e0-4b57-8bd2-922c91e5a5b6/iepi_a_12325068_f0001.jpg)
Environmentally induced epigenetic mechanisms acting on the genome during prenatal and early postnatal development facilitate genome-wide changes in the epigenome that alter transcription at distinct developmental time points. The mRNA alterations that occur cause deficits in multiple processes including cortical migration, chromatin remodeling, transcriptional regulation, immune-response regulation and the formation of synaptic connections. Genome-wide association and whole exome sequencing studies have identified a large number of genes linked with ASD that encode proteins that function in synapse formation, transcriptional regulation and chromatin-remodeling pathways [Citation12]. Current findings, highlighted in this review, indicate that there is considerable overlap between ASD-susceptibility genes and the mRNAs impacted by various environmental/epigenetic influences. Both environmental factors and genetic mutations alter the transcriptome during neurodevelopment. We propose that idiopathic ASD is the consequence of environmentally induced epigenetic influences operating on sufficient numbers of ASD susceptibility genes to produce the ASD phenotype. Individuals with mutations in ASD susceptibility genes are also subject to these same in utero environmental influences (arrow from altered genome). In contrast, syndromic ASD is characterized by genetic mutations that occur in so-called network hub genes [Citation25]. In network theory, hub genes refer to highly interconnected nodes that are often times responsible for regulating key biological pathways or directing the cellular response to a given stimulus [Citation185]. For example, FMR1 encodes the RNA-binding protein, FMRP which is deficient in Fragile X, an ASD-related syndrome. FMRP regulates the translation of a set of over 800 plasticity-related genes in response to stimulation by the neurotransmitter glutamate [Citation186]. Mutations in FMR1 cause Fragile X syndrome, which is a syndromic ASD. The etiology and symptomatology of various syndromic ASD disorders has recently been reviewed [Citation8,Citation9].
ASD: Autism spectrum disorder; CNV: Copy number variant.
![Figure 2. Epigenetic impact of the prenatal environment.Environmentally induced epigenetic mechanisms acting on the genome during prenatal and early postnatal development facilitate genome-wide changes in the epigenome that alter transcription at distinct developmental time points. The mRNA alterations that occur cause deficits in multiple processes including cortical migration, chromatin remodeling, transcriptional regulation, immune-response regulation and the formation of synaptic connections. Genome-wide association and whole exome sequencing studies have identified a large number of genes linked with ASD that encode proteins that function in synapse formation, transcriptional regulation and chromatin-remodeling pathways [Citation12]. Current findings, highlighted in this review, indicate that there is considerable overlap between ASD-susceptibility genes and the mRNAs impacted by various environmental/epigenetic influences. Both environmental factors and genetic mutations alter the transcriptome during neurodevelopment. We propose that idiopathic ASD is the consequence of environmentally induced epigenetic influences operating on sufficient numbers of ASD susceptibility genes to produce the ASD phenotype. Individuals with mutations in ASD susceptibility genes are also subject to these same in utero environmental influences (arrow from altered genome). In contrast, syndromic ASD is characterized by genetic mutations that occur in so-called network hub genes [Citation25]. In network theory, hub genes refer to highly interconnected nodes that are often times responsible for regulating key biological pathways or directing the cellular response to a given stimulus [Citation185]. For example, FMR1 encodes the RNA-binding protein, FMRP which is deficient in Fragile X, an ASD-related syndrome. FMRP regulates the translation of a set of over 800 plasticity-related genes in response to stimulation by the neurotransmitter glutamate [Citation186]. Mutations in FMR1 cause Fragile X syndrome, which is a syndromic ASD. The etiology and symptomatology of various syndromic ASD disorders has recently been reviewed [Citation8,Citation9].ASD: Autism spectrum disorder; CNV: Copy number variant.](/cms/asset/699703e5-369d-4ca7-9061-5202eab4963d/iepi_a_12325068_f0002.jpg)