Dr. Janine LaSalle discusses some of the potential epigenetics mechanisms involved in autism spectrum disorders in this recorded webinar.
This webinar is brought to you with support from Porvair Filtration Group. Check out their line of innovative ChIP kits and reagents at chromatrap.com
Epigenetics of Autism
Autism is an increasingly common disorder of complex etiology, affected by multiple genetic and environmental influences. Epigenetic mechanisms represent a critical link at the interface between genetic and environmental factors and as such, they affect a wide range of human disorders with developmental origins. Methylation of CpG dinucleotides and methyl-specific binding proteins are part of an epigenetic pathway essential for parental imprinting and chromatin dynamics during normal brain development. Recent next-generation sequencing efforts have now given us access to the whole human DNA methylome at base resolution, revealing striking differences in the epigenomic landscapes of pluripotent and lineage-committed human cells. In brief, these studies have confirmed that the human genome is highly methylated (>70% methylation) except for CpG island promoters that are strongly depleted for DNA methylation.
However, large-scale partially methylated domains (PMDs, <70% average methylation) are observed in human fibroblasts, adipose, and placenta, in contrast to the rest of the genome which is in highly methylated domains (HMDs, >70% average methylation).
Using bisulfite conversion followed by high-throughput sequencing (MethylC-seq), we developed a novel hidden Markov model (HMM) to computationally map the genomic locations of PMDs in both cell types and found that genomic regions marked by cell line specific PMDs contain genes that are expressed in a tissue-specific manner, with PMDs being a mark of repressed transcription. Genes contained within neuronal highly methylated domains were significantly enriched for calcium signaling, synaptic transmission and neuron differentiation functions. Autism candidate genes were significantly enriched within N-HMD regions and include genes such as CHRNA7, GABRB3, CNTNAP2, EN2, NLGN3, HTR2A, RELN, GRIK3, KCNN3, and NRXN1. Our results suggest that these large-scale methylation domain maps could be relevant to interpreting and directing future investigations into genetic and epigenetic etiologies of autism.
Perinatal exposure of mutant mice to the common flame retardant PBDE at a dose comparable to average human levels negatively impacted sociability, learning, and early growth of female offspring. A high PBDE dose at the level of the highest observed human exposure negatively impacted fertility. Female offspring perinatally exposed to PBDE showed reduced DNA methylation in brain in adulthood, corresponding to the defects in social and cognitive learning behaviors. Interaction with MeCP2 genetic mutation was specific to females and different depending on the behavioral test, with a reversing interaction observed in a short-term social memory test, but a compounding interaction observed in a long-term memory test.
These and other studies suggest a new paradigm of “integrative genetics” in which genetic variation and differences in genomic size may be impacted by dietary and environmental factors that influence the genomic saturation of DNA methylation.
Human genomes are highly repetitive, but the interface of large-scale genomic differences with environmental factors that alter the DNA methylome such as dietary folate is under-explored. In addition to obvious direct effects of some environmental toxins on the genome by causing chromosomal breaks, non-mutagenic toxin exposures correlate with DNA hypomethylation that can lead to rearrangements between repeats or increased retrotransposition. Since human neurodevelopment appears to be particularly sensitive to alterations in epigenetic pathways, a further focus will be on how developing neurons may be particularly impacted by even subtle alterations to DNA methylation and proposing new directions towards understanding the quixotic etiology of autism by integrative genomic approaches.