L49: Epigenetic Phenomena Flashcards
What is Beckwith-Wiedemann syndrome?
- Example of uniparental disomy disorder - Incidence = 1/13000 - Some types arise when child inherits homologues of a portion of chromosome 11 from father. - S&S: overabundance of IGF2, leads to kidney, adrenal and liver problems, resulting in severe hypoglycemia. Characterized by microcephaly, macroglossia (large tongue) and umbilical hernia. Susceptible to childhood cancer.
Describe the effects of 5-azacytidine on genome methylation
- Hypermethylation can be reversed by this drug, which is a DNMT inhibitor. Treatment serves to allow for re-activation of silenced tumor suppressor genes
What is uniparental disomy? What are the effects of this?
- Zygote with only maternally or paternally imprinted homologues of a chromosome - This leads to problems with gene dosage (overabundance of one gene, lack of another for example).
Explain the parent-of-origin effect observed in Prader-Willi and Angelman syndromes
- Prader-Willi: deletion exists from paternal chromosome 15, mothers is imprinted and therefore silenced. Incidence = 1/10-50K. Characterized by obesity, excessive food seeking behavior, hypogonadism, mental retardation, small hands and feet - Angelman: deletion exists on maternal chromosome 15, fathers is imprinted and therefore silenced. Incidence = 1/15K. Characterized by unusual facial features – large mandible and open mouth, seizures, movement and gait disorders, mental retardation, excessive laughter and absence of speech.
Implication of epigenetic changes in T-Cells as implicated in SLE
- SLE is caused by epigenetic changes in T-cells - This is an autoimmune disease with incidence = 1/2000 affecting females 8-10 times more than males - In this condition, antibodies against nuclear components are produced. - Global hypomethylation of the T-cell genome is seen in these patients - DNMT inhibitor treatment on T-cells causes SLE-like phenotypes
Explain the function of boundary elements
- Boundary elements aka chromatin barriers serve to separate active and inactive genomic regions
Classes of drugs that counteract malignancy resulting from DNA methylation and histone acetylation
- HDAC inhibitors - DNMT inhibitors
Contrast de-novo and maintenance methylation
De-novo DNA methylation - Methylation is introduced into an unmethylated strand of DNA by DNA methyltransferases DNMT3a and b Maintenance - Pattern of DNA methylation is maintained through mitosis by DNA methyltransferase DNMT1 - During S-phase, DNA pol synthesizes a non-methylated strand from the methylated template strand - New double-strand consists of a methylated and non-methylated strands transiently. DNMT1 methylates the non-methylated strand based on what is seen on the template
Explain how epigenetic changes play a role in the development of cancer
- Global hypomethylation of DNA outside of CpG islands is seen in most cancers - Hypomethylation causes genomic instability and therefore elevated transposon activity, resulting in chromosomal abnormalities. This causes cancer. - Hypermethylation of CpG islands in promoter can shut down tumor suppressor genes – sometimes seen in non-familial breast cancers
How does methylation silence transcription?
- Methylation of DNA occurs on cytosine residues in CpG islands - After methylation occurs, methylcytosine binding proteins bind methylcytosine. - MBPs interact with repressors of transcription leading to transcriptional block and HDACs that lead to chromatin condensation
Explain the significance of CpG islands for gene expression
- Methylation of DNA occurs on cytosine residues in areas rich in CG known as CpG islands - CpG islands are found upstream of genes close to the 5’ region - Methylation acts to silence part of the genome
What is Rett Syndrome?
- X-linked dominant disorder mapped to mutations in the gene for methyl-cytosine binding protein MECP2 - Mutation leads to loss of transcriptional silencing - Symptoms: autism-like symptoms, repetitive teeth grinding and hand-wringing, motor problems and characteristic gait. Onset age 6-18 months
What is imprinting? Explain the time and effects of imprinting
- Imprinting is a form of DNA silencing that marks a chromosome as having come from the paternal or maternal parent. Why care? Transcriptional activities of paternal and maternal chromosomes are different. - Imprinting takes place during gametogenesis. Chromosomal regions are silenced by DNA methylation and histone deacetylation. This persists throughout the life of the individual. - Parent-of-origin imprint is erased and rewritten during gametogenesis. Female will reprogram both her chromosomes to make them look like maternal chromosomes. Male reprograms both his chromosomes to make them look like paternal chromosomes
List histone modifications that are possible
- Acetylation - Methylation - Phosphorylation - Ubiquitination
Explain the effect of hypomethylation on genome stability
- Hypomethylation reactivates transposable elements (jumping genes) that lead to somatic recombination and genomic instability.
