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Imprinting in the news

Imprinting in the news. Potential blood test to screen for colon cancer. Colon Cancer- 3 rd most deadly cancer in America. Loss of Imprinting (LOI) of the Igf2 gene correlates with colon cancer. Result= Maternal Igf2 gene is turned on. With family history- 5X more likely to show LOI

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Imprinting in the news

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  1. Imprinting in the news Potential blood test to screen for colon cancer • Colon Cancer- 3rd most deadly cancer in America Loss of Imprinting (LOI) of the Igf2 gene correlates with colon cancer Result= Maternal Igf2 gene is turned on • With family history- 5X more likely to show LOI • Polyps detected- 3X more likely to show LOI • Personal history- 22X more likely to show LOI Source- AP News, March 14, 2003

  2. Definition- Differential expression of two parental alleles Only occurs in eutherians (placental, nonmarsupial) mammals Not in other vertebrates Of 20-some identified genes, most are involved in 1. Fetal growth Igf2, IgF2r, H19, Grb1 2. Brain development Prader-Willi syndrome (PS), Angelman syndromes (AS), Peg1/Mest Genomic Imprinting

  3. Categories of imprinted genes 1. Fetal growth genes- Insulin-like growth factor-like II (IGF2) response pathway • IGF2 • Igf2r • Grb10 • H19 • Gnas • Rasgrf • Mash2 • Why?- Embryo develops in a parasite-like relationship with mother.

  4. Categories of imprinted genes 2. Brain development- • Prader Willi Syndrome- paternal chromosome deletion • Angelman Syndrome- maternal chromosome deletion • Why?- Any ideas?

  5. Prader-Willi Syndrome • 1 in 15,000 live births • mostly sporatic • deletion at 15 q11-q13 • diagnosis at 2 years • obesity, short, small hands/feet, unusual facial features, mild mental retardation • compulsive overeaters

  6. A typical Prader-Willi patient • Prader Willi Syndrome- Due to paternal chromosome deletion

  7. Angelman Syndrome • 1 in 25,000 live births • mostly sporatic • 80 % have deletion at 15q11-q13 • Specifically mutation of UBE3A gene

  8. Angelman Syndrome • Speech impairment • None or minimal use of words • Receptive and non-verbal communication skills higher than verbal ones • Movement or balance disorder, usually ataxia of gait • Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor • easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span

  9. Angelman Syndrome • Angelman Syndrome- maternal chromosome deletion Or an imprinting defect Normal Or 2 paternal chromosomes

  10. Functional studies- Chimeras Definitions Implant into pseudopregnant female + • Androgenotes- two paternal genomes • Gynogenotes- two maternal genomes • Both of these (andro- and gyno-genotes) result in an imbalance (increase or decrease) of expression of imprinted genes • Result is developmental abnormalities chimera

  11. Functional studies- Chimeras • Androgenetic- oversized, small brains • Gynogenetic- growth retarded, large brains (cortex) • Conclude- imprinted genes contribute to rapid expansion of the cortex

  12. Turner syndrome Only 1 X chromosome • 1/2000; females only • short stature, failure to mature sexually • Often learning difficulties, skeletal abnormalities, hearing loss, liver dysfunction, heart and kidney abnormalities, infertility, and thyroid dysfunction • Females with single X chromosome • If X from father- better verbal and social skills than if X from mother • Conclude- Some imprinted genes on X escape inactivation only if from father

  13. Parent Offspring Conflict Hypothesis (Haig hypothesis) • Conflict between male and female over allocation of maternal resources to offspring • Dad uses imprinting to direct all resources to immediate offspring (not future litters) • Mom uses imprinting to allocate resources to multiple litters • Thus, predict paternally expressed genes would promote growth, maternally expressed genes should slow it down • Prediction mostly hold true • Example- Igf2 (paternally expressed)-if defective=40% reduction in growth

  14. Parent Offspring Conflict Hypothesis (Haig hypothesis) Example – The Igf2 gene and its receptor Igf2r • Igf2 (paternally expressed)-if defective=40% reduction in growth • Igf2r (Igf2 receptor)- if defective=increase growth • Igf2-/Igf2r- = normal Another test- Ask if imprinting fails to occur in a monogomous species The Beach mouse is entirely monogomous ….but imprinting still occurs, contrary to model

  15. Is the imprint erased during embryogenesis?

  16. Is the imprint erased during embryogenesis? • Observation-Aparthenogenetic embryos generated from from immature embryos proceed to late developmental stage that from using mature embryos- • Answer- Probably Two general mechanisms proposed: • Passive process via direct methylation of Dnmt1 • Active process via specific demethylation

  17. Is the imprint erased during embryogenesis? • Evidence in support • Biallelic expression of imprinted genes occurs in primordial germ cells • Igf2r imprinting control region (ICR) is methylated in E8 embryos, but unmethylated E12.5 embryos • Dnmt1 is at high levels during Igf2r maternal imprint • Answer- Probably

  18. How are imprinted genes silenced? S. Tilghman, Cell 96:185

  19. How are imprinted genes silenced? Dnmt-/- mice- Many imprinted genes (e.g. H19) reactivated ..but, Igf2 and Igf2r are silenced Mechanism- Methylation interferes with transcription factor binding Problems with model- 1. Promoters of silent Igf2 and Igf2r alleles are unmethylated 2. One gene, Mash2, is unaffected by loss of methylation S. Tilghman, Cell 96:185

  20. How are imprinted genes silenced? Mechanism- Promoters compete for a single enhancer Igf2 H19 Problem with model- Both H19 and Igf2 are expressed if H19 gene replaced with luciferase S. Tilghman, Cell 96:185

  21. How are imprinted genes silenced? Epigenetic marker binds to unmethylated DNA • Mechanism- • Methylation serves two purposes • Inactivate a gene (e.g. H19) • Prevent binding of epigenetic marker so that Igf2 is activated Igf2 H19 Epigenetic insulator prevents enhancer from “talking to” Igf2 Evidence in support: if delete insulator element- both Igf2 and H19 expressed S. Tilghman, Cell 96:185

  22. Evidence for chromatin boundary mechanism Deletion of ICR- both genes expressed Identify protein (called CTCF) that binds ICR CTCF cannot bind methylated DNA Thorvaldsen and Bartolmei, Science 288:2145, 2000

  23. How are imprinted genes silenced? Mechanism- Antisense transcription of unmethylated chromosome blocks sense strand transcription Mechanism- Antisense RNA blocks sense strand transcription S. Tilghman, Cell 96:185

  24. Prader-Willi Syndrome Normal expression patterns = ON

  25. Prader-Willi Syndrome Normal expression patterns = ON In Prader-Willi deletion, maternal and paternal copies are silent In Angelman, many genes are activated, but UBE3A is silenced

  26. Prader-Willi Syndrome Proposed mechanism of SNPRN imprinting Female allele Imprintor gene IMPRINT SNSIS SNRPN gene 1 3 2 RNA (BD RNA) Dnmt Male allele Imprintor gene Active SNSIS SNRPN gene RNA (BD RNA) In Prader Wille, the Switch Initiator Site (SNSIS) is mutated in paternal chromosome, such that it can’t bind BD RNA

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