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43 Cards in this Set
- Front
- Back
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DNA & Chromosomes
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Single, continuous piece of DNA in a chromosome; every human diploid cell contains 23 pairs of chromosomes (46 in total) 22 pairs of autosomal chromosomes, 1 pair of sex chromosomes; packing ratio of 10,000:1
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Chromatin
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DNA + associated proteins
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Histone
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specialized proteins that associate with/package DNA; positive charge of histones interacts with negatively charged back bone of DNA, N-terminal segment can be modified by key enzymes, having a profound effect on DNA compaction and gene transcription
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Nucleosome
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complex of histone proteins and supercoiled DNA; 146bp of DNA wrapped twice around histone core (histone octomer); 2x H2A, H2B, H3, H4
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Histones--H1
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linker histone; not involved in octomer, binds to linker DNA and connects nucleosomes
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Euchromatin
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Histones are present, but DNA is opened enough that genes are active and transcription proteins can come in
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Histone code hypothesis
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activity of a chromatin region depends on the degree of chemical modification of histone tails; docking sites to recruit non-histone proteins, alter interactions of neighboring nucleosomes. Tags can be methyl groups, acetyl groups, ubiquitine, phosphate groups; they get put onto primarily the tail of the histone, and will dictate whether the histone will be in the heterochromatin or euchromatin formation
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Epigenetics
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Study of heritable changes in gene expression or phenotype caused by mechanisms other than changes in underlying DNA sequence; coined by CH Waddington in 1942
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Epigenome
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Overall epigenetic state of a cell; functionally relevant modifications to the genome that do not involve a change in nucleotide sequence (activate or silence genes). Epigenetic changes are preserved when cells divide (mitosis); can be maintained throughout a lifetime and passed on to the next generation
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Twin studies (Epigenetics)
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Research in 80 sets of monozygotic twins; DNA is marked in different ways with methyl, differences are much more pronounced in older twins.
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Agouti mouse model (Epigenetics)
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Genetically identical mice where one has the Agouti gene activated--yellow fur coat and obesity result. The other with the silenced gene has a brown coat and normal weight. Modulate expression of the agouti gene in offspring through enrichment of maternal diet with methyl rich supplements (i.e. folic acid)
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DNA methylation
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No methylation of CpG= gene "on", tissue specific genes and housekeeping genes. Methylation of CpG= gene "off", non-tissue-specific genes, silent DNA. Methylation of CpG done through DNA methyltransferases (DNMTs)--knock it out=lethal in animals, but over-expression=cancer in humans. Methyl groups acquired through diet (folate, methionine, selenium); methylation pattern maintained through cell replication (sits on cysteine)
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Methylation of histones
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Adding of methyl groups to lysine or arginine residues on histone tails; typically a marker for gene silencing (recruitment of DNA methylases to methylate DNA around methylated histone, adding to silencing effect). Methylation of histones via histone methyltransferases (HMTs/KMTs)
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Acetylation of histones
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(backbone of DNA is negatively charged) Acetylation of lysine residues on histone tails, removing positive charge of tail, loosening the histone-DNA complex and exposing DNA so genes can be activated (transcription). Acetyl groups can be removed; not permanent like methylation (transient changes)
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Histone acetyltransferase (HAT/KAT) and histone deacetyltransferase (HDAC)
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Activity of these enzymes to either acetylate or deacetylate histones can be regulated by several environmental factors. Acetyl Co-A is donor for acetyl groups, can change rapidly.
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Long non-coding RNA (lncRNA)
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Sequence-specific molecules that can guide protein complexes to specific sites in the chromatin and orchestrate transcriptional repression (important role in X-chromosome inactivation, imprinting)
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Epigenetic reprogramming
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erasure and remodeling of epigenetic marks (usually stick with you for life; except acetyl modification which is transient)
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Stages in which epigenome undergoes reprogramming
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1. Gametogenesis: want eggs and sperm to get a fresh start; de-methylation, X-chromosome reactivation, imprinting
2. Pre-implantation: once fertilization occurs, we try to erase epigenome so that fetus gets fresh start; de-methylation, X-chromosome inactivation, and tissue-specific methylation |
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Morphogenesis
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Tissue-specific methylation
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Genome wide demethylation
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Some marks can escape this process; these are the effects that get passed down generation to generation
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X-chromosome reactivation
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Randomly turning off one X chromosome in every cell. If that egg cell happens to get that one X chromosome that is inactivated, it can have a serious problem. therefore, this X gets reactivated to save the developing embryo
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Imprinting
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gene expression occurring from 1 allele only; parent-of-origin-specific (imprinted genes are not equally expressed). occurs in ~ 80 genes, which is less than 1% of our genome (embryonic/placental development, growth and metabolism). Activation/silencing due to epigenetic modifications (DNA methylation, histone modification).
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Example of imprinting
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gene located at maternally imprinted locus; gene from mother turned off, gene from father turned on
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Why imprint?
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Males: want to make sure that their baby is the biggest/dominant/strongest
females: it doesn't make sense for only some of your litter to survive, so she can try to regulate their growth |
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Steps of imprinting
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1. erasure 2. imprint established according to the sex of the individual; ie. sperm=paternal imprint 3. imprint is maintained during fertilization and pre-implantation 4. imprint is maintained in somatic cells for a lifetime
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Effects of imprinting
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Imprinted genes are especially sensitive to environmental signals; single active copies, so no back up.
Environmental signals can also affect the imprinting process itself, impacting gene expression in next gen |
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Imprinting: pre-implantation
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X-chromosome inactivation: imprinted genes do not get erased in the efforts to erase epigenome to give fetus a fresh start; if embryo has 2 X's, one will be turned off, while the mother exposes the embryo to environment to help tag this embryo's genes with methyl groups
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X chromosome inactivation
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blocking protein protects 1 X from being target for epigenetic modification; non-coding RNA coat other X chromosome that will be silenced. Note: ~25% of human genes on the X chromosome escape inactivation, also on Y chromosome (2 copies is norm)
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X-linked diseases
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more likely to be expressed in males because they only have 1 X, compared to women who have 2 and a better chance of having the defective X copy silenced. Turner syndrome (XO), Klinefelter syndrom (XXY)
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Y chromosome
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encodes mostly for sex-related proteins. less genomic function than X chromosome in general
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Prenatal smoke exposure
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associated with reduced birth weight, poor developmental and psychological outcomes, risk for diseases and behavioral disorders later in life
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Nested cohort study
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N=348; ongoing children's health study; global and gene specific differences in CpG DNA methylation patterns associated with in utero exposure to maternal smoking; genes related to cancer progression and immune response
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Adversity/stress in childhood
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Associated with psychiatric disorders (depression, anxiety), drug and alcohol abuse.
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Animal models with low levels of maternal care
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increased methylation of the glucocorticoid receptor (GR) gene (receptor that is important in how we respond to stress); exaggerated hormonal and behavioral responses to stress
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Cross-sectional analysis
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N=99; disruption/lack of adequate nurturing (parental loss, childhood maltreatment, poor parental care) lead to increased CpG methylation of the GR gene
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High-fat diet (HFD)
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Associated with metabolic disturbances and obesity, CVD, cancer.
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Randomized cross-over design (studying HFD)
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N=21, HFD for 5 days, collection of skeletal muscle biopsies; HFD introduced widespread DNA methylation changes affecting 45% of studied genes (6508 genes); inflammation, reproductive system, and cancer changes. Methylation changes were only partly reversed after 6-8 weeks
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Epigenetics and disease: cancer
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most have adult onset; genome is static from birth, but epigenome is not. Role for epigenetics in the etiology of cancer; mechanisms: 1. DNA methylation (hyper vs. hypo-methylation) 2. Histone mod (methylation and acetylation) 3. Disruption of the epigenetic machinery (DNMTs, HDACs) 4. Loss of imprinting (IGF-2=Wilms Tumor)
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DNA methylation in cancer
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hyper methylation: tumor suppressor genes (TSG) and repair genes that inhibit cell growth are underexpressed. Hypo methylation: oncogenes overexpressed; leads to increased growth/division
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Histone modification in cancer
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gene rich areas--methylation and de-acetylation
non-coding areas--de-methylation and acetylation increased methylation + decreased acetylation result in over-expression of oncogenes and under-expression of TSGs |
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Disrupted epigenetic machinery in cancer
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different tumours/cancers are a result of mutations in epigenetic modifying proteins that result in abnormal modifications. irregular and dangerous growth and division occurs
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Loss of imprinting in cancer
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Bi-allelic expression of a normally imprinted gene; 2x amount of gene expressed (ex. Wilms tumor): mother's version is normally imprinted (therefore silenced); but if it's not then this double expression of genes leads to overgrowth
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Cancer therapy and epigenetics
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epigenetic profiles for screening, prognosis. Pharmacological targeting of epigenetic machinery: DNMT inhibitors (Azacitidine, Decitabine) and HDAC inhibitors (Vorinostat, Romidepsin)--alone not really effective, but if the patient is treated with these then chemo, their success rates are higher than if they didn't take these before chemo.
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