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Chapter 6 Epigenetics and Disease
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Epigenetics Are chemical modifications of deoxyribonucleic acid (DNA) sequences that alter the expression of genes, resulting in disease and phenotypic variations (upon genetics). Types of epigenetic modifications DNA methylation Histone modification Microribonucleic acids (miRNAs) or mature miRNAs [miRs]) Specific environmental or nongenetic factors, such as diet and exposure to certain chemicals, can affect epigenetics.
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Epigenetics (cont’d)
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DNA Methylation Is the attachment of a methyl group to a cytosine base that is followed by a guanine base; also known as CpG dinucleotide. Causes a gene to become transcriptionally inactive or silent. When DNA sequence in the promoter region of a gene becomes heavily methylated, DNA is less likely to be transcribed into messenger RNA (mRNA). Aberrant methylation: Is the silencing of tumor suppressor genes in cancer development. Is a key component of X-inactivation.
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DNA Methylation (cont’d) Process
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Histone Modification Results Histone acetylation and deacetylation Alterations in chromatin Chromatin compaction and organization normally help regulate gene expression to maintain cell identity. Chromatin structure must be controlled in self-renewing and differentiated cells in cell-renewal systems. Histone hypoacetylation, condensation of chromatin, and methylation interactions Inhibit the binding of proteins that promote transcription; the gene becomes transcriptionally inactive.
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Microribonucleic Acids Are short nucleotides derived from introns of protein-coding genes. Can also be transcribed from noncoding DNA located among genes. Perform critical functions during development and cell differentiation. Regulate diverse signaling pathways. Gene expression can be regulated by changes in miRNAs and other noncoding RNAs (ncRNAs).
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Microribonucleic Acids (cont’d) ncRNAs regulate gene expression by RNA interference Gene co-suppression Gene silencing Imprinting DNA demethylation Oncomir Is an miRNA that stimulates cancer development and progression. Acts as either an oncogene or tumor-suppressor gene.
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Microribonucleic Acids (cont’d) Question 1 Which statement is most correct regarding miRNAs? miRNAs Result from the attachment of a methyl group to a cytosine base, followed by a guanine base. Enhance X-inactivation, silencing genes on the X chromosome. Become the hereditary transmission of epigenetic changes to successive generations. Are short nucleotides derived from introns of protein-coding genes.
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Epigenetics and Development Embryonic stem cells Pluripotent Can become any cell that is needed for development. Key event in early embryogenesis Differential epigenetic modification (including extensive methylation) of specific DNA nucleotide sequences Ensures that specific genes are expressed only in the cells and tissue types in which their gene products are needed. Helps determine the fate of each cell; that is, the type of cell it becomes, such as a myocyte, neuron, or fibroblast
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Twin Studies Provide Insights on Epigenetic Modification Are a powerful means for testing epigenetic effects. Compare methylation and other signatures of epigenetic modification in identical (monozygotic) twin pairs, because their DNA sequences are essentially the same. As twins age, differences increase in methylation patterns of the DNA sequences of somatic cells.
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Twin Studies Provide Insights on Epigenetic Modification (cont’d) Twins with significant lifestyle differences (e.g., smoking versus non-smoking) Accumulated larger numbers of differences in their methylation patterns. Became more different as a result of epigenetic changes, which in turn affected the expression of genes. These results, along with findings generated in animal studies, suggest that changes in epigenetic patterns may be an important part of the aging process.
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Epigenetics and Cancer DNA methylation and cancer tumor cells Exhibit hypomethylation (decreased methylation). Increases activity of oncogenes. Hypomethylation increases as tumors progress from benign neoplasms to malignancy.
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Epigenetics and Cancer (cont’d) DNA methylation and cancer tumor cells (cont’d) Exhibit hypermethylation in promoter regions of tumor-suppressor genes. Ability to inhibit tumor formation: Decreases Promoter region of the RB1: Can cause retinoblastoma BRCA1: can lead to inherited breast cancer VHL promoter region: associated with von Hippel-Lindau disease, in which renal cell carcinomas frequently occur
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Epigenetics and Cancer (cont’d) DNA methylation and cancer tumor cells (cont’d) Methylation of the promoter region of a gene: MLH1 When MLH1 becomes inactive, damaged DNA accumulates, eventually resulting in colon tumors. Is the major cause of one form of inherited colon cancer—hereditary nonpolyposis colorectal cancer.
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Epigenetics and Cancer (cont’d) miRNAs and cancer Hypermethylation observed in miRNA genes, which encode small (22 base pair) RNA molecules that bind to the ends of mRNAs, degrade them and prevent translation. Hypermethylation of specific subgroups of miRNAs is associated with tumorigenesis. When miRNA genes are methylated, their mRNA targets are overexpressed; this overexpression has been associated with metastasis.
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Epigenetics and Cancer (cont’d)
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Epigenetics and Cancer (cont’d) Strategies for treating epigenetic disease Epigenetic modifications can be reversed. Demethylating agent: 5-azacytidine is used as the treatment of leukemia and myelodysplastic syndrome. Histone deacetylase (HDAC) inhibitors: Counteracts the removal of acetyl groups from histone proteins, which can silence the activity of tumor-suppressor genes. Are used in the treatment of T-cell lymphomas. Major challenge: Is to develop drugs that target only the genes responsible for a specific cancer.
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Epigenetics and Cancer (cont’d) Question 2 Which statement by the nurse indicates an accurate understanding of epigenetics and cancer? “Hypomethylation of the promoter region of the RB1 gene is often observed in retinoblastoma.” “Hypomethylation increases as tumors progress from benign neoplasms to malignancy.” “Hypomethylation of specific subgroups of miRNAs is associated with tumorigenesis.” “Hypomethylation occurs when HDAC inhibitors are administered for cancer.”
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Genomic Imprinting Is the process of gene silencing, in which genes are predictably silenced, depending on which parent transmits them. Transcriptionally silenced genes: Imprinted Are usually heavily methylated. Diseases from abnormal imprinting patterns Prader-Willi and Angelman syndromes Beckwith-Wiedemann syndrome Russell-Silver syndrome
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Prader-Willi and Angelman Syndromes Prader-Willi syndrome Is the deletion of approximately 4 million base (Mb) pairs of the long arm of chromosome 15. Is inherited from the father. Clinical manifestations Short stature Hypotonia Small hands and feet Obesity Mild-to-moderate mental retardation Hypogonadism
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Prader-Willi and Angelman Syndromes (cont’d) Angelman syndrome Has the same deletion of approximately 4 Mb pairs of the long arm of chromosome 15. Is inherited from the mother. Clinical manifestations Severe mental retardation Seizures Ataxic gait
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Prader-Willi and Angelman Syndromes (cont’d) Prader-Willi vs Angelman Syndromes
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Prader-Willi and Angelman Syndromes (cont’d) Pathophysiologic processes The 4-Mb deletion (the critical region) contains several genes that are normally transcribed only on the copy of chromosome 15 that is inherited from the father. Several genes in this region are normally active on only one chromosome copy. If the single active copy of one of these genes is lost because of a chromosome deletion, then no gene product is produced, resulting in disease.
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Prader-Willi and Angelman Syndromes (cont’d)
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Prader-Willi and Angelman Syndromes (cont’d) Pedigrees
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Beckwith-Wiedemann Syndrome Is an overgrowth condition accompanied by an increased predisposition to cancer. Overexpresses a gene product. Is usually identifiable at birth. Is large for gestational age; exhibits neonatal hypoglycemia, large tongue, creases on the ear lobe, omphalocele, and hemihyperplasia. Presents an increased risk of developing Wilms tumor or hepatoblastoma. Screening at regular intervals is an important part of management.
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Beckwith-Wiedemann Syndrome (cont’d) Approximately 20% to 30% of incidences are caused by the inheritance of: Two copies of a chromosome from the father and no copy of the chromosome from the mother Uniparental disomy, affecting chromosome 11 Several genes on the short arm of chromosome 11 are imprinted on either the paternally or maternally transmitted chromosome. Are found on two separate, differentially methylated regions (DMRs). DMR1: Gene that encodes insulin-like growth factor 2 (IGF2)
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Beckwith-Wiedemann Syndrome (cont’d)
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Russell-Silver Syndrome Causes the downregulation of IGF2, resulting in diminished growth. Growth retardation; proportionate short stature; leg-length discrepancy; small, triangular-shaped face Approximately one-third are caused by imprinting abnormalities of chromosome 11p15.5 that lead to the downregulation of IGF2. Maternal uniparental disomy cause another 10% of those with the syndrome.
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Diseases from Abnormal Imprinting Patterns Question 3 Which pathophysiologic process is occurring in a person with Beckwith-Wiedemann syndrome? Missing chromosome 15 Missing gene product Downregulation of IGF2 Extra copies of active IGF2
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Future Directions Experimental observations are clarifying the roles of epigenetic states in determining cell fates and disease phenotypes. Possibilities for reversing the epigenetic abnormalities and preventing their establishment in utero are being identified.
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Unit II: Genes and Gene-Environment Interaction—Case Study A 2-month-old infant is admitted to the hospital after several days of vomiting after feedings. The child is diagnosed with pyloric stenosis.
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Unit II: Genes and Gene-Environment Interaction—Case Study (cont’d) Discussion Questions This disease does not follow the inheritance patterns of single-gene disease. This type of disease is considered to be: Multifactorial Congenital Following a bell-shaped distribution model Following a liability of threshold model
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Unit II: Genes and Gene-Environment Interaction—Case Study (cont’d) Discussion Questions Although the mother is staying with the child after surgical correction, her husband comes to visit and brings their other child. This child has Prader-Willi syndrome. This disease is an example of Imprinting Trisomy Hypermethylation Nondisjunction