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What is meant by the term epigenetics?
Epi in EPIgenetics refers to Above, or in addition to genetics. The modern definition is: the study of CHANGES in gene expression NOT caused by changes in DNA sequence.
Name the two most common types of epigenetic changes and the most commonly employed method to study each change?
- 1. DNA methylation: acts to inhibit transcription by interfering with transcription factors.
- DNA method: Sodium Bisulfate modification, leads to deamination of unmethylated cytosine to uracil
- 2. Histone modifications (post translationally) such as acetylation and methylation of various amino acid residues. Meth tightly packs chromatin whereas acet helps histones come apart to help access to transcription factors
- Histone method: Chromatin Immunoprecipitation (ChIP), using antibodies to target specific targets
What are the four most common effects of epigenetic changes?
- 1. X-inactivation
- 2. Changes in gene expression
- 3. Genomic imprinting
- 4. Disease onset, such as autoimmune disorders, Type 2 diabetes and CANCER
Briefly summarize the general mechanism of DNA methylation including reference to CpG islands. What change in gene expression is DNA methylation most commonly associated with?
- DNA methylation starts with the 5’ cytosine. DNA methyltransferase is used to transfer a methyl group from SAM to Cytosine to make 5’ MeC. This usually occurs where Cytosine nucleotide occurs next to a Guanine nucleotide. These CpG are known to be grouped together at high density, mostly associated with PROMOTER areas in gene expression.
- Methylation associated mostly with gene silencing
Describe two possible explanations for gene silencing.
- 1. The 5’ MeC methyl group extends to the MAJOR groove of DNA, INHIBITING transcription by interfering with TRANSCRIPTION FACTOR Binding proteins that act to recruit activators
- 2. Recruiting of these methyl-binding proteins will act to RECRUIT transcription co-repressor complexes
In humans, DNA methylation is essential for embryonic development. The demethylation and remethylation cycle is thought to erase previous paternal imprints and reestablish sex-specific imprints. Name and define the two mechanisms of DNA demethylation
- 2 MECHANISMS of DNA demethylation: ACTIVE and PASSIVE demethylation
- 1. Active demethylation: occurs through DIRECT enzymatic removal of DNA modification independent of DNA replication. This can involve a deamination reaction
- 2. Passive demethylation: occurs via replication coupled DILUTION due to LACK of re-establishment of DNA modification on daughter strand DNA after synthesis.
Briefly describe how the demethylation cycle may lead to transgenerational epigenetics.
Transgenerational epigenetics occurs during the two stages of 5mC erasure. In this case, Methyl tags that SILENCE genes slip through tags that are not in parental strand and these methyl tags are passed to OFFSPRING
What is Beckwith-Wiedemann Syndrome (BWS)? Why is this syndrome relevant to the topic of epigenetics? Be sure to include the different epigenetic changes leading to BWS and the genes affected.
- BWS is an imprinting disorders resulting from EPIGENETIC events or mutations, affecting genes at chromosome 11, leading to cancer (inhibition of cell proliferation). At least 3 major features or 2 major features and 1 minor feature must be present for a diagnosis. Major features include positive family history, macroglossia (enlarged tongue), cleft palate
- Some patients with BWS have abnormal DNA meth on chrom 11…leading to tumor suppressor to be inactive
- Gain of methylation at imprinting clubst 1 (IC1) on chrom 11 leads to OVERexpression of IGF2
What is the primary purpose of the paper by Cooper et al. (2005), and why is the study significant in diagnosis of BWS? What are the important conclusions of the study?
- Primary purpose of study: to identify genotype-phenotype correlations to optimize ways to manage treatment strategies. This study used molecular analysis to do this.
- The study found: significant DIFFERENCES between molecular subtypes of BWS, showing BWS represents a spectrum of disorders. These molecular subtypes allowed for more accurate prognostic predictions and ENHANCES management of BWS children.
What is Lynch Syndrome? What is its underlying cause? Why is this syndrome relevant to the topic of epigenetics? Be sure to include the names of the genes associated with this syndrome and their general function. Your answer should also indicate that you understand the meaning and use of the terms hemiallelic expression and constitutional epimutation.
- Lynch syndrome is a hereditary syndrome leading to different types of cancer, such as liver, stomach, prostate and most NOTABLY Colorectal cancer. It is usually associated with DNA MISMACH REPAIR deficit
- Genes are involved in constitutional epimutation, which is germline mutation that does not occur because of a change in DNA sequence, but have early onset cancer consistent with familiar cancer. These mutations are in the following genes that are involved in DNA mismatch repair and tumor suppression
- MSH2, DAPK1, KILLIN and
- MLH1: homologue of E. coli DNA mismatch repair gene mutL, hypermethylation occurs to result in GENE silencing, due to a defect in DNA mismatch repair where promoter stays methylated
There are 2 types of constitutive hemi-allelic hypermethylation in relation to Lynch syndrome:
- 1. Primary: dense hemi-allelic methylation ERASED in germline or follows Non-Mendelian inheritance pattern
- 2. Secondary: demonstrates somatic mosaicism, heterogeneticty in methylation level between alleles or tissues and may show Mendelian or Non-mendelian
What was the focus of the paper by Hitchens et al. (2011) and what were the important conclusions of their study? Be Specific!
- The focus was in looking at constitutional MLH1 epimutations in a cancer affected family. This mutation,, associated with methylation, although erased in spermatozoa, was reinstated in somatic cells of next generation. In these haplotypes they found certain single nucleotide substitutions, one which was the probable cause of this mutation.
- The single nucleotide substitution is: c.-27C>A variant.