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Genes and genomics
Published in Firdos Alam Khan, Biotechnology Fundamentals, 2018
In addition to epigenetic alterations, specific mutations affecting components of the epigenetic pathway have been identified that are responsible for several syndromes: DNMT3B in immunodeficiency, centromeric instability, and facial anomalies syndrome, MECP2 in the Rett syndrome, ATRX in ATR-X syndrome, and DNA repeats in facioscapulohumeral muscular dystrophy. In Rett syndrome, for example, MECP2 encodes a protein that binds to methylated DNA; mutations in this protein cause abnormal gene expression patterns within the first year of life. Girls with the Rett syndrome display reduced brain growth, loss of developmental milestones, and profound mental disabilities. Similarly, the ATR-X syndrome also includes severe developmental deficiencies due to loss of ATRX, a protein involved in maintaining the condensed, inactive state of DNA. Together, this constellation of clinical pediatric syndromes is associated with alterations in genes and chromosomal regions necessary for proper neurological and physical development.
Inorganic Chemical Pollutants
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Altered BDF transcripts have been reported in Rett syndrome patients, a neurodevelopmental disorder characterized by mutations of MeCP2,407,408 and BDNF levels are decreased in the brain of MeCP2 mutant mice.409,410 Other studies have shown that reduced phosphorylation of MeCP2 at S421 reduces dendritic branching and alters the morphology of dendritic spines,384 effects that have also been observed in the Pb2+-exposed brain.411,422 They should note that the phosphorylation of MeCP2 at S421 is selective for CaMKII and no other kinases,384 and they have previously shown that CaMKII activity and protein levels are significantly reduced in the hippocampus of rats exposed to Pb2+ during development.372 Because MeCP2 is a master regulator of transcription, the present findings suggest that the transcriptional activity of other genes whose promoters are regulated by MeCP2 may also be affected by Pb2+ exposure.
Genetic and Epigenetic Considerations in iPSC Technology
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Methyl-CpG binding domain (MBD) is a functional domain that interacts with 5mC DNA and is identified in five proteins, MeCP2 and MBD1, MBD2, MBD3, and MBD4. MeCP2 is especially a critical factor for neuronal development and functions as a transcriptional repressor by recruiting NCoR/SMRT repressive complex (45). Loss of MeCP2 leads to neurodevelopmental disorder, the Rett syndrome (RTT), and several groups, including our laboratory, succeeded in generation of iPSCs from RTT patients (RTT-iPSC) (20,46). RTT-iPSCs show distinguishable transcriptome profiles from normal iPSCs, indicating that MeCP2 also affects transcriptional regulation in the stem cell stage. Furthermore, the deletion of MeCP2 increases the efficiency of iPSC generation (47). Overall, 5mC shows negative effect on iPSC reprogramming but is required to establish stem cells with proper differentiation capacities.
Epigenetic modifications associated with pathophysiological effects of lead exposure
Published in Journal of Environmental Science and Health, Part C, 2019
Madiha Khalid, Mohammad Abdollahi
DNMT1 and DNMT3a through their overlapping roles are important for the normal development of the nervous system, its function, and maturation, while a deficiency of these will result into aberrant synaptic plasticity and defect in learning and memory.107 Pb, via these proteins, can influence DNA methylation-mediated gene regulation which is important for neural cell differentiation and cognitive functions including learning and memory.108 MeCP2, a DNA binding protein, binds to methylated CpG dinucleotides and regulates the transcription of various genes.109 Previously, reported aberrant MeCP2 methylation or expression has been linked to Rett syndrome,110 cognitive and behavioral disorders (e.g., learning disabilities, autism, mental retardation, and ADHD) and synaptic plasticity.111–113 Sex-specific differences in gene expression were observed in the hippocampus and frontal cortex,114,115 such effects have been found to express differently during different developmental periods of Pb exposure.116,117 Both sex and sex hormone levels influence genomic methylation 118 which may influence Pb-induced interactions with specific genes and transcriptional regulation. There is little information about the influence of sex in genomic and epigenomic regulations, requiring more investigations. Pb exposure in rats showed a nonlinear dose–response relationship (i.e., U-shaped) in the hippocampus.119,120 Some human studies reported a decline in memory and learning among Pb-exposed individuals.121–123 Similarly, a study among children with a low Pb exposure level showed a greater impact on IQ scores than children with a higher Pb exposure level,124 which may be due to the involvement of different mechanisms at different Pb exposure levels.64 Aforementioned facts suggest that the regulation of DNA methyltransferases and DNA binding proteins are complex under different pathological conditions as under normal physiological conditions and tend to behave differently in males and females during the development of the nervous system.