Principles of Clinical Epigenetics PDF

Principles of Clinical Epigenetics Common epigenetics terms with definitions CpG or CpG site: a cytosine guanine dinucleotide (i.e., a C nucleotide followed by a G nucleotide in the DNA sequence oriented 5′ to 3′). Cytosines in CpG dinucleotides can be methylated, making 5- methylcytosines. C...

Principles of Clinical Epigenetics Common epigenetics terms with definitions CpG or CpG site: a cytosine guanine dinucleotide (i.e., a C nucleotide followed by a G nucleotide in the DNA sequence oriented 5′ to 3′). Cytosines in CpG dinucleotides can be methylated, making 5- methylcytosines. CpG methylation is the most abundant form of DNA methylation, although there is non-CpG methylation. DMR (differentially methylated region): a set of CpGs within a defined locus, which differs between samples; samples used to identify DMRs may differ by tissue type, phenotype, exposure, etc. DMRs are regarded as possible functional regions involved in gene transcriptional regulation, especially when they overlap gene regulatory regions, such as promoters or enhancers. DNA methylation: the addition of a methyl group, typically to the cytosine in a CpG at position C5, creating 5-methylcytosines. Addition of methyl groups to DNA is carried out by DNA methyltransferases. Epigenome: the complete set of (described and undescribed) epigenetic marks. Each cell type carries a unique epigenome, which contributes to cellular identity. Epimutation: a disease-related change in DNA methylation, often occurring at an imprinted locus. EWAS (epigenome-wide association analysis): a research methodology that takes its name from genome-wide association analysis, in which variation in an epigenetic mark is assessed against a phenotype of interest. Imprinted domain: a cluster of imprinted genes and associated regulatory elements, including an imprinting center. Imprinting center: regulatory regions of varying DNA methylation levels established in the Epigenetics Modifications to DNA, such as DNA methylation (5-methylcytosine [5mC]). Post-translational modifications of histone proteins (acetylation, phosphorylation, and methylation). Noncanonical histone variants Noncoding RNAs (e.g., long noncoding RNAs and microRNAs) X chromosome inactivation. Mechanisms of Epigenetic Regulation Epigenetic Writers, Erasers, and Readers Writers: Enzymes that add epigenetic marks (e.g., DNA methyltransferases for DNA methylation). Erasers: Enzymes that remove epigenetic marks (e.g., histone deacetylases). Readers: Proteins that recognize and interpret epigenetic marks to modulate transcription.  Genomic Imprinting A fundamental principle of Mendelian genetics is that the function of an allele in the F1 generation is not influenced by whether it comes from the mother or the father. Certain genes in mammals are exceptions to this rule and do not follow this pattern. The term "imprinting" refers to the fact that the silencing of either the maternal or paternal copy of an imprinted gene is not due to a change in the DNA nucleotide sequence. Instead, it involves sex-specific methylation of specific DNA regions known as imprinting control regions (ICRs). As a result of epigenetic modification, the transcription of an allele depends on the parent that transmits it is known as Genomic Imprinting Parental Allele-Specific In genomic imprinting, the copy of a gene an individual inherits from one parent is silenced Imprinting. For imprinted genes, either the maternal or paternal (transcriptionally inactive permanently), while the copy inherited from the other parent is active. allele is methylated significantly such that only one copy produces protein More than 120 of imprinted genes are paternally imprinted (the allele inherited from the father is not transcribed/silenced). Majority of imprinting genes are involved in controlling embryo growth and development, including development of placenta. Clinical Epigenetics The field of research that studies how epigenetic modifications affect gene expression and contribute to health and disease. Understanding diseases such as cancer, autoimmune disorders, neurodegenerative diseases, and metabolic conditions. Uncover how environmental factors, lifestyle, and other external influences can modify epigenetic markers, leading to the development of novel diagnostics, treatments, and therapeutic interventions. Recent discoveries Identification of large number of rare mendelian disorders which are caused by sequence variants in genes that encode epigenetic regulators and imprinting disorders. Identifying epigenetic patterns that aid in diagnosing rare Mendelian disorders, imprinting disorders, and various types of cancer. Finding common thread of atypical neurodevelopment across many of these disorders, which highlight the importance of clinical epigenetics to the field of medicine. Evaluating the effectiveness of new treatments and exploring therapeutic options that specifically target epigenetic mechanisms DNA Methylation reprogramming during Human Development Diet: Nutrients and vitamins, such as folate, vitamin B12, and methionine, can impact DNA methylation, influencing gene expression. Toxins and Pollutants: Exposure to chemicals like tobacco smoke, heavy metals, pesticides, or air pollution can induce epigenetic modifications. Stress: Psychological stress can trigger epigenetic changes, particularly through the regulation of stress-responsive genes. Exercise: Physical activity can modify the epigenome, especially in genes involved in metabolism, inflammation, and muscle development. Sleep: Sleep patterns can influence epigenetic marks, with disruptions in sleep leading to changes in genes related to circadian rhythms, immune function, and metabolism. Microbiome: The gut microbiome also interacts with the epigenome. Metabolites produced by gut bacteria can affect histone modifications and DNA methylation, influencing genes related to immune function, inflammation, and digestion.  Environment-driven modification of the epigenome Agouti gene in mice controls fur color via melanin production. During hair follicle cell development, this promoter results in gene activation. Insertion of an intracisternal A-particle (IAP) retrotransposon in the Agouti gene results in expression of this gene in all cells. The phenotype of these mutant mice includes yellow fur, obesity, type II diabetes, and predisposition to tumors. Mice with the IAP insertion can have a range of pan-cellular Agouti expression, and the associated phenotypes are dependent on the levels of DNA methylation at the IAP. Diet rich in methyl donors fed to pregnant Agouti mice can alter the expression of the Agouti gene in the offspring, which will in turn impact long-term health. Mothers heterozygous for the Avy allele, when crossed with heterozygous males and fed with a diet high in methyl donors, will - intracisternal A-particle (IAP) more frequently produce healthy brown Avy offspring, who carry high levels DNA methylation acting to repress this gene.  Ideograms of human imprinted genes. - A small percentage of human genes - undergo genomic imprinting. - Many of the imprinted genes play key roles in regulating growth and development. - Majority of imprinted genes are found in clusters, called imprinted domains, in specific chromosome regions. - More than 120 imprinted genes have been identified across the human genome.  Parental Allele-Specific Imprinting and disease Imprinting disturbances due to epigenetics have been reported in classical disorders including Prader–Willi, Angelman and Beckwith– Wiedemann syndromes Prader-Willi and Angelman syndromes are caused by the same autosomal deletion: a small deletion in the q11-13 region of chromosome 15. When the deletion is inherited from the father, the child develops Prader-Willi syndrome When the same deletion come from the mother, the child has Angelman syndrome Copyright © The McGraw-Hill Companies, Inc. The explanation is that several genes are in the region of these deletions and are imprinted differently. In the case of Angelman syndrome the gene involved is UBE3A. Dysregulation of imprinted genes on 11p15 can cause opposite phenotypes Russel Silver Syndrome: a rare congenital growth disorder characterized by intrauterine growth restriction (IUGR) and continued poor postnatal growth. Beckwith–Wiedemann syndrome: a congenital overgrowth disorder caused by abnormal regulation of gene expression in specific regions of chromosome 11p15. Increased risk of childhood cancer like Wilms tumor and hepatoblastoma Different phenotypes determined by parent-of-origin– specific imprinting. Disorders Involving Unstable Repeat Expansions Normal size FMR1 Vs Expansion of the FMR1 CGG repeat Normal size FMR1 alleles, the FMR1 promotor is unmethylated allows access of transcription factors to the FMR1 promoter leading to transcription of FMRP rare cases of males with full FMR1 expansion and normal cognition, in whom the FMR1 promoter has been shown to remain unmethylated. Expansion of the FMR1 CGG repeat triggers a cascade of epigenetic events methylation of the FMR1 promotor, which leads to reduced or absent production of the fragile X mental retardation protein (FMRP). - Mendelian disorders of the epigenetic machinery Over 70 genes with defined epigenetic domains (reader, writer, eraser, remodeler, middle icons) have been linked to mendelian phenotypes. Most of the genes cause disease in the heterozygous state. There are a small number of genes that regulate DNA methylation in contrast to those that regulate histones Appendix  Normal Igf2 allele is expressed Paternal chromosome Maternal chromosome Normal Igf2 allele is not expressed Wild-type mouse (normal size) Mutant Igf2 allele Mutant Igf2 allele inherited from mother inherited from father Normal size mouse Dwarf mouse (wild type) (mutant) Normal Igf2 allele Mutant Igf2 allele is expressed is expressed Mutant Igf2 allele Normal Igf2 allele is not expressed is not expressed Insulator methylation mechanism: Some insulator contains CpG sequences, and the functions of these insulators can be controlled by DNA methylation. Imprinting of Igf2 works through methylation of an insulator that lies between the Igf2 promoter and its enhancer. The unmethylated insulator on the maternal chromosome is functional: it binds CTCF. As result, the enhancer on the maternal chromosome cannot interact with the promoter of Igf2, and the Igf2 gene is silenced. In contrast, on the paternal chromosome the insulator is methylated, which prevents it from binding CTCF. CpG island methylation/ncRNA: The ICRs of some imprinting genes contain a noncoding RNA (ncRNA) whose transcription is controlled by CpG island. On the paternal Igfr2 chromosome, a ncRNA called Air is transcribed from a promoter within an intron of Igfr2, but in opposite direction to Igfr2. The Air ncRNA is an antisense transcript whose expression prevents the transcription of Igfr2. In contrast, on the maternal chromosome, a CpG island that controls Air transcription is methylated, silencing expression of Air and thus permitting Igfr2 transcription Copyright © The McGraw-Hill Companies, Inc. “Insulator” is the name given to a class of DNA sequence elements that possess a common ability to protect genes from inappropriate signals emanating from their surrounding environment.