Chapter 6: Epigenetics and Disease

Twins with 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 suggest that changes in epigenetic patterns may be an important part of the aging process.

Which statement by the nurse indicates an accurate understanding of epigenetics and cancer? 1. "Hypomethylation of the promoter region of the RB1 gene is often observed in retinoblastoma." 2. "Hypomethylation increases as tumors progress from benign neoplasms to malignancy." 3. "Hypomethylation of specific subgroups of miRNAs is associated with tumorigenesis." 4. "Hypomethylation occurs when HDAC inhibitors are administered for cancer."

*2. Hypomethylation increases as tumors progress from benign neoplasms to malignancy.* Tumor cells typically exhibit hypomethylation (decreased methylation), which can increase the activity of oncogenes. 1. Hypermethylation of the promoter region of the RB1 gene is often seen in retinoblastoma. 3. Hypermethylation of specific subgroups of micoRNAs is associated with tumorigenesis. 4. Another class of drugs, histone deacetylase (HDAC) inhibitors, counteracts the removal of acetyl groups from histone proteins which can silence the activity of tumor-suppressor genes.

Which statement is most correct regarding miRNAs? miRNAs 1.Result from the attachment of a methyl group to a cytosine base, followed by a guanine base. 2.Enhance X-inactivation, silencing genes on the X chromosome. 3.Become the hereditary transmission of epigenetic changes to successive generations. 4.Are short nucleotides derived from introns of protein-coding genes.

*4. are short nucleotides derived from introns of protein coding genes.* Micro-ribonucleic acids (miRNAs or miRs) are encoded by short DNA sequences (approximately 22 nucleotides) located in introns of genes or transcribed from noncoding DNA located between genes. 1. DNA methylation results from attachment of a methyl group to a cytosine base that is followed by a guanine base (a "CpG dinucleotide"). 2. DNA methylation is a key component of X-inactivation, the transcriptional silencing of genes on the X chromosome. 3. The hereditary transmission of epigenetic changes to successive generations has been termed epigenetic transgenerational inheritance.

Beckwith-Wiedemann Syndrome

-An overgrowth condition accompanied by an increased predisposition to cancer. -Overexpresses a gene product. -Is usually identifiable at birth. --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.

Beckwith-Wiedemann Syndrome Pathogenesis

-Approximately 20% to 30% of incidences are caused by uniparental disomy --Inheritance of two copies of chromosome 11 from the father and no copy of the chromosome from the mother -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) active on paternal chromosome

Epigenetics

-Are chemical modifications of deoxyribonucleic acid (DNA) sequences that alter the expression of genes, resulting in disease and phenotypic variations (upon genetics).

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).*

Russel-Silver Syndrome

-Characterized by 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.

Twin Studies

-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.

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.

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

Treatment of 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.

CA and Hypermethylation

-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 -When MLH1 becomes inactive, damaged DNA accumulates, eventually resulting in colon tumors. Is the major cause of inherited colon cancer—hereditary nonpolyposis colorectal cancer.

Angelman Syndrome Pathogenesis

-Genes encode a ligase for protein degradation during brain development, thus resulting in mental retardation and ataxia. -In brain tissue, genes are active only on the chromosome inherited from mother; maternally transmitted deletion removes the single active copy.

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

Histone Modification

-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.

miRNAs in CA

-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.

Oncomir

-Is an miRNA that stimulates cancer development and progression. --Alter the activity of an oncogene or tumor-suppressor gene.

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.

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

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

Embryonic Stem Cells

-Pluripotent: can become any cell that is needed for development

Noncoding RNAs (ncRNAs)

-Regulate gene expression by: RNA interference Gene co-suppression Gene silencing Imprinting DNA demethylation

Prader-Willi Pathogenesis

-Several genes in the critical region are transcribed only on the chromosome transmitted by the father. -A paternally transmitted deletion removes the only active copies of these genes, producing the features of this syndrome.

CA and Hypomethylation

-Tumor cells often exhibit decreased methylation genome-wide, increases activity of oncogenes -Hypomethylation increases as tumors progress from benign neoplasms to malignancy.

Which pathophysiologic process is occurring in a person with Beckwith-Wiedemann syndrome? 1.Missing chromosome 15 2.Missing gene product 3.Downregulation of IGF2 4.Extra copies of active IGF2

4. *Extra copies of active IGF2*. 1. A well-known disease example of imprinting is associated with a deletion of about 4 million base pairs (Mb) of the long arm of chromosome 15. If it is from the father it is called Prader-Willi; if it is from the mother it is called Angelman syndrome. 2. in contrast to Prader-Willi and Angelman syndromes, which are produced by a missing gene product, Beckwith-Wiedemann syndrome is caused, in part, by over-expression of a gene product. 3. Downregulation of IGF2 causes the diminished growth seen in Russell-Silver syndrome.

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 1.Imprinting 2.Trisomy 3.Hypermethylation 4.Nondisjunction

ANS: 1 Imprinting is a process of gene silencing in which genes are silenced depending on which parent transmits them. Prader-Willie is inherited from the father and is a deletion of a portion of the long arm of chromosome 15. 2.Trisomy is the duplication of chromosome material, whereas Prader-Willie is a monosomy. 3.Methylation is one of several epigenetic mechanisms that cells use to control gene expression. Hypermethylation is associated with tumor production. 4.Nondisjunction in an error in which homologous chromosomes or sister chromatids fail to separate normally during meiosis or mitosis.

This disease does not follow the inheritance patterns of single-gene disease. This type of disease is considered to be: 1.Multifactorial 2.Congenital 3.Following a bell-shaped distribution model 4.Following a liability of threshold model

ANS: 4. Those diseases that do not follow the bell-shaped distribution appear to be either present or absent in individuals. They do not follow the inheritance patterns of single=gene disease. They follow a liability distribution that states that a threshold of liability must be crossed before the disease is expressed. Pyloric stenosis is an example of this type of disease. 1. Multifactorial diseases are caused by complex genetic and environmental factors. 2. Congenital diseases are those present at birth. Most of these are multifactorial in etiology. 3. Traits caused by the additive effects of many genetic and environmental factors, they tend to follow a normal or bell-shaped distribution in populations.