W11L3 fri epigenetic 2 Flashcards
Imprinting of cluster, parental vs maternal
-Gene silencing by boundaries. H19 is expressed from the maternal chromosome only; Igf2 from the paternal.
- The two genes share an enhancer region downstream of H19.
-The differentially methylated region (DMR) of H19 is a boundary element, controlled by DNA methylation.
-CTCF protein binds to the unmethylated maternal ICR, preventing the enhancers downstream of the H19 gene interacting with Igf2 and so silencing it.
- The paternal DMR is methylated preventing binding of CTCF. This allows enhancers to contact paternal Igf2, allowing the gene to be transcribed.
-The paternal H19 gene is silenced by methylation.
-Deletion of DMR removes imprinting of IGF2 and H19
H19 lnc
-H19 lnc RNA controls gene expression by recruiting MBD1 (turn on in maternal)
-MBD1 bind to methylation region of the genome, ensure greater methylation (reinforcement)
IGF2 imprinting and disease
-failure to imprint methylation lead to uncontrolled cell growth and proliferation
-over imprintation can lead to loss of cellular adhesion, EMT
Why do we have impriting
- Must have an evolutionary advantage
- Genetic / epigenetic tug of war
- Overall strategy for fitness advantage for the paternal and maternal genomes is different
Genome wide epigenetic landscape
- Genes throughout the genome regulated by epigenetic marks
- NOT sex specific (differs from imprinting and X-inactivation)
- Same mechanisms apply
- Plastic and subject to environmental conditions
- Heritable
Epigenetic marks, what can it tell us
- different histone tail modification have a specific affect on the expression of the gene
ChIP-Seq
- Chromatin Immunoprecipitation (ChIP) used to identify histone bound regions
- Isolated DNA is then deep sequenced
- Mapped to reference genome
Genome Wide Epigenetic scans result
- Critical new advancement in genomics
- Majority of disease mutations do not occur in protein coding regions (only 1.5% of genome)
Genome Wide scans in ESCs
- Identified active ESC (Class 1) genes and Poised (Class 2) genes that drive later embryogenesis
Non-coding RNAs and epigenetics
- Increasingly complex genome
- 1.5% of genome protein coding – 98.5% junk?
- Majority of genome is transcribed
- ChIP Seq and transcriptome sequencing identifying new RNA classes
Lnc and ESC epigenetic
- In total ~30% of all lncRNAs in ESCs associate with chromatin modifiers
- 23% with PRC2 alone
- Most associate with multiple modifiers
Genome wide epigenetic landscape
- High plasticity for Immediateresponse (in a single generation) to changing environment
– In utero exposures / nutrition
– Exogenous chemicals
– Altered cell states (cancer)
Diet and inheritance in human
-The children of women who were pregnant during the famine that hit the Netherlands at the end of the Second World War were smaller than normal. This effect can still be seen from the next generation even if mother receive normal nutrition
-found that the grandchildren of well-fed adolescents had a greater risk of dying from diabetes, whereas those descended from famine survivors were less likely to die of heart disease
Variation in coat colour in isogenic yellow agouti mice
dams fed normal diet or diet supplemented with the methyl donors and cofactors folic acid, vitamin B12, choline chloride, and anhydrous betaine gave birth to a different distribution of coat colours
-less methyl donor, yellow and slightly mottled coat (higer risk of obesity and tumors)
-more methyl donor diet, meavily motted or pseudo agouti
Diethylstilbestrol (DES)
Synthetic estrogen
* Drug given to women between 1930s-1970s to prevent miscarriage and premature birth
* >10 million pregnancies treated worldwide
* Caused reproductive cancers and abnormalities
