Role of epigenetics in Rett syndrome Rett syndrome (RTT; MIM 312750). There are other neurodevelopmental dis-. Epigenetics, Autism Spectrum, and Neurodevelopmental Disorders - Europe PMC Article“Epi- ” is derived from the Greek for “over” or “above”, and the term “epigenetics”, coined by Waddington, refers to mechanisms “above” the DNA sequences that regulate gene expression . The sequence of a person’s genome alone may be inadequate when we try to understand the combined effect of genetic make up and environment on the phenotype of children with developmental disorders. Regulation of neuronal structure and function through epigenetic mechanisms is believed to be critical in the development of the nervous system. Disruption or alteration of this process may cause an array of neurodevelopmental disorders, including ASDs . The role of epigenetics in autism has only emerged in the last few years, and represents a growing area of research . The nucleosome consists of a 1. DNA segment wrapped around an octamer of core histone proteins made up of a pair of H3–H4 dimers and a pair of H2. Autism spectrum disorders & other developmental disorders. Classification of Diseases and Related Autism spectrum disorders. Neurodevelopmental impairments in communication.A–H2. B dimers, connected by linker DNA. Epigenetic modifications include biochemical modifications of DNA (methylation of cytosine residues at Cp.
G islands) and post- translational modification of histone proteins. These epigenetic marks are considered to be permanent within a cell all through development, and are accurately replicated in daughter cells through mitosis. Autism spectrum disorders. Epigenetics and Autism. For diagnosis of neurodevelopmental disorders: challenges and opportunities. Epigenetic modifications affect DNA–protein interactions resulting in large- scale changes in chromatin structure or modulation of gene transcription. Genomic Imprinting in ASDOne specific form of epigenetic regulation of gene expression is genomic imprinting. The term genomic imprinting was first coined by Helen Crouse in 1. In imprinted regions, either the paternal or the maternal allele of selected genes is silenced. Normal development requires bi- parental inheritance and expression of genes from both chromosomes. A gene is “maternally imprinted” if the maternal allele is silenced, and “paternally imprinted” if the paternal allele is silenced. The imprinting pattern is established in germ cells. Many genes are ubiquitously imprinted in the body; however, there are genes that have tissue- specific or activity- specific imprinting patterns . An extreme example of genomic imprinting is X- inactivation in females, the process by which 1 of the 2 X- chromosomes is completely silenced and forms the Barr body . One characteristic of imprinted genes is the presence of differentially methylated regions (DMRs), where the 2 parental chromosomes are differentially marked by DNA methylation . DMRs act as imprinting control regions (ICRs), loci that are required for imprinting of all genes within a cluster . De novo DNA cytosine- 5- methyltransferase- 3- alpha catalyzes methylation of cytosine residues within Cp. G dinucleotides in both germ cells and in pre- implantation embryos. Imprinted genes are thought to play an important role in embryonic development . Expression of imprinted genes is high in both brain and placenta. There are approximately 7. More maternally methylated DMRs and ICRs have been identified than paternally methylated DMRs and ICRs . In mice, about 1. Many of these imprinted loci have been shown to influence neuronal differentiation, behavior, or susceptibility to neurological disease . Evidence linking genomic imprinting to neurodevelopmental disorders including ASD comes from the study of Prader–Willi syndrome (PWS) and Angelman syndrome (AS). Although clinically distinct, both disorders are caused by mutations within chromosome 1. PWS/AS region). The phenotype is dependent on which parental chromosome carries the genetic modification. Analysis of chromosome 1. PWS/AS region . AS is characterized by delayed development, intellectual disability, speech impairment, epilepsy, puppet- like ataxic movement, prognathism, tongue protrusion, paroxysms of laughter, and abnormal sleep patterns. Mutation or deletion of the maternal gene ubiquitin protein ligase E3. A (UBE3. A) causes AS. UBE3. A encodes a homologous to E6- associated protein C terminus domain E3 ubiquitin ligase. Deletions (~6 Mb in size, including UBE3. A) in the maternal chromosome 1. AS cases, and point mutations in maternal UBE3. A account for 1. 0–1. The remaining cases are caused by uniparental disomy or mutations within the imprinting control regions. In humans and mice, UBE3. A is bi- allelically expressed in most tissues. In neurons, owing to tissue- specific paternal imprinting, the maternal allele alone is expressed, while the paternal allele is epigenetically silenced . Analysis of “knock- in” mice in which a UBE3. AYFP (yellow fluorescent protein) fusion gene was inserted into the UBE3. A locus revealed that UBE3. A was enriched in nuclei and dendrites of neurons. Study of YFP expression in the brain when the fusion gene was maternally or paternally inherited clearly demonstrated paternal imprinting of UBE3. A in neurons of the hippocampus, cortex, thalamus, olfactory bulb, and cerebellum . Biallelic expression was seen in glial cells. The molecular mechanism by which the paternal UBE3. A gene is imprinted is complex (Fig. The UBE3. A promoter region is unmethylated in both the maternal and paternal chromosomes. This implies that differential methylation of the UBE3. A promoter is not the mechanism for paternal imprinting in the brain. Antisense RNA- mediated epigenetic silencing of many genes has been reported . The UBE3. A antisense RNA transcript (UBE3. A- ATS) is thought to mediate the silencing of the paternal UBE3. A allele . UBE3. A- ATS is a large transcript (5. SNRPN–SNURF–UBE3. A gene cluster in chromosome 1. The UBE3. A- ATS is expressed exclusively from the paternal allele in neurons; in these same neurons, the sense UBE3. A messenger RNA (m. RNA) is expressed from the maternal allele. UBE3. A- ATS is an atypical RNA polymerase II transcript, and functions in cis to suppress paternal UBE3. A expression . The paternal antisense transcript is positively regulated by the PWS imprinting center (PWS- IC) and deletion of this PWS- IC causes increased expression of the paternal sense UBE3. A m. RNA . Thus, the paternal PWS- IC promotes expression of genes from the paternal SNRPN–SNURF–UBE3. A cluster, while at the same time repressing paternal UBE3. A gene expression via an antisense RNA mechanism . Inhibition of UBE3. A- ATS expression is a potential therapeutic target for patients with AS carrying a mutant maternal allele . In an alternate model, it has been proposed that expression of UBE3. A- ATS induces histone modifications within the paternal UBE3. A locus that aborts transcriptional elongation of sense UBE3. A, resulting in truncated, inactive UBE3. A m. RNAs . This locus controls maternal and paternal specific expression of (A) protein- coding genes ubiquitin protein.. In a recent study, Huang et al. They used the UBE3. A–YFP knock- in mouse model as a reporter of UBE3. A imprinting . In cultured embryonic cortical neurons prepared from these mice, UBE3. A–YFP expression was suppressed when UBE3. A–YFP was paternally inherited (UBE3. Am+/p. YFP), but was expressed when UBE3. A–YFP was maternally inherited (UBE3. Am. YFP/p+). They used neurons from UBE3. Am+/p. YFP animals to screen for drugs that upregulated YFP fluorescence. Unexpectedly, topoisomerase inhibitors (including toptecan and irinotecan) were found to unsilence the paternal UBE3. A allele. They then tested topotecan in an AS mouse model (maternally- derived UBE3. A- null allele) and found that topotecan up- regulated expression of active UBE3. A in cultured neurons from AS mice. When given intrathecally (intraventricular injections or injection into the spinal subarachnoid space) into AS mice, topotecan, unsilenced and upregulated expression of the paternal UBE3. A allele in several regions of the nervous system. This effect was long lasting, suggesting that these were potential therapeutic agents for treatment of AS. Prader- Willi Syndrome PWS is characterized by hypotonia and failure to thrive in the immediate postnatal period. Appearing later are the more typical features of hyperphagia resulting in obesity, hypogonadism, mild- to- moderate mental retardation, behavior problems, and autistic features. The prevalence of PWS is 1 in 1. Microdeletion (5–6- Mb region) in the paternal chromosome 1. PWS. Approximately 2. PWS patients have maternal uniparental disomy, where both copies of chromosome 1. A mutation within the PWS- IC is seen in almost 5 % of patients. Less than 1 % of patients have a chromosomal rearrangement resulting in a breakpoint within or deletion of the paternal 1. Each of these genetic lesions leads to the loss of differential methylation at PWS- IC, resulting in the loss of expression of paternally- derived alleles. Deficiency in these paternal transcripts is implicated in PWS, but the function of most of the encoded proteins is not completely understood. Lack of the paternally expressed SNORD1. RNA has been shown to result in a PWS or PWS- like phenotype . Imbalance of 1. 5q. ASD cases. This can disrupt normal parental homologue pairing, DNA methylation patterns, and gene expression patterns within 1. Features of autism, along with cognitive impairment, anxiety, and hyperactivity are seen in 1. Penetrance of the autism phenotype is complete in patients with idic. Paternally- inherited duplication of this region very rarely predisposes an individual to ASD . Studies in postmortem brain samples have shown that, despite increased maternal dosage, the expression of imprinted genes within this region (SNRPN, NDN, small nucleolar RNAs) is reduced. The 1. 5q. 11- 1. GABA) receptor genes (GABRB3, GABRA5, and GABRG3). The expression of these genes is also reduced. In contrast, studies in transformed lymphocytes and postmortem brain tissue from idic. UBE3. A expression (m. RNA and protein) is increased, proportional to the increase in gene dosage . It is suggested that the epigenetic alteration due to long- range chromatin organization might contribute to these gene expression abnormalities .
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