MARCO - epigenetics Flashcards
Epigenetics
refers to external modifications to DNA that turn genes “on” or “off” without changing the DNA sequence.
* Epigenetic changes alter the physical structure of DNA.
* Epigenetic modifications can be inherited
* Ex: DNA & histone modifications
Epigenetics and cancer:
- incorrect histone modifications resulting in aberrant histone labelling on chromosomes, along with incorrect DNA modifications, will cause aberrant gene expression. This can then lead to cancer.
- An epigenetic change that silences a tumour suppressor gene could lead to uncontrolled cellular growth
- An epigenetic change that “turns off” genes that help repair damaged DNA can lead to an increase in DNA damage, which in turn, increases cancer risk
Ex. of disruptive epigenetic change: Incorrect genomic methylation - Hypermethylation of the CpG island within the promoter region of the GSTP1 gene, resulting in aberrant silencing of the gene, has been found to occur in more than 90% of prostate cancers
Epigenetic driven phenotype: Tortoiseshell pattern of cat fur
- Occurs as a result of X-inactivation which. involves Xist lncRNA that recruits PRC2 to lay down repressive histone modifications, inactivating 1 copy of the female X chromosomes.
- The black and orange allele for fur color reside on X chromosome
- For females, depending on which X chromosome is inactivated in each cell, the colors of each cell will be different. This results in a scattering pattern of orange and black fur among female cats.
- For males, they only contain 1 allele of the fur color due to the presence of only 1 X chromosome, so they’ll either be all black or all orange. Therefore, all tortoiseshell cats are female
Agouti mice
- Involves methylation of Agouti gene promotor.
- Agouti gene is only expressed briefly during mice developmental period & silenced directly after by methylation of its promotor.
- When a mouse Agouti gene promotor is normally methylated, the gene will be correctly silenced, resulting in a normal mouse that has a brown coat with low disease risk.
- When a mouse agouti gene promotor is abnormally unmethylated, the agouti gene will be aberrantly expressed (not correctly silenced), and the mouse will have a yellow coat, become obese, and will be prone to diabetes and cancer
- Therefore, a mouse that is fed a methyl rich diet will have normal methylation of the agouti gene & develop into a healthy mouse. A mouse that is fed with low methyl diet, thus have less methyl group for methylation of agouti gene promotor, will develop into a yellow, disease-risk mouse.
Epigenetics and twin
Twins are a good way to study epigenetics because they have the exact same DNA, so any differences observed have risen due to epigenetics
When twins chromosome’s epigenetic pattern is labelled with different dyes (red and green), the result clearly shows that as the twins grow up, they adopt different epigenetic modification patterns, resulting in different phenotypes/ disease susceptibility.
- This is observed from regions with overlapping modifications (shown in yellow) decreasing over time.
-This further supports that epigenetics depend on the environment ex. diets, smoking that can change modification patterns.
Erasing of epigenetics
- During fertilization, methylation is largely erased and continue to be lost as the embryo develops to form a blastocyst.
- The methylation marks are converted to hydroxymethylation which is then progressively diluted out as the cells divide.
- This allows for high plasticity & reprogramming, so the cells in the blastocyst stage can act as stem cells (can differentiate into any cell type).
- At a later stage, the chromosome can then decide which epigenetic tag to adopt to regulate their genes, so they are modified again to specialize into different cell types.
- Therefore, there are mechanisms in which cells remember which genes need to later be methylated.
-Research has found that some rare methylation can escape this reprogramming process. Thus, allows for inheritance of some epigenetics traits that arise in parents by environment.
Inheritance of epigenetics - smoking mother
Smoking can alter the mother’s epigenetic modifications. Failure to reprogram those alterations can be passed down to the baby as well, affecting their health conditions.
Inheritance of epigenetics - dutch famine
- During the Dutch famine of 1944-1945, the west of the Netherlands suffered from an extreme lack of food.
- People during that time then developed less methylation on the insulin-like growth factor II (IGF2). This drives their metabolism to be set at a more economical level to cope for the famine.
- Children who were conceived then also inherited the epigenetic modification.
- These inherited epigenetic modifications continue to have long term effects. At an old age, those children suffer more frequently from obesity and cardio-vascular diseases. They also have increased methylation of five other genes, among which are associated with cholesterol transport and ageing, as well as schizophrenia However, the mechanism of epigenetics inheritance remains elusive and are still debated among scientists.
Imprinting
- For most genes we inherit two working copies - one maternal and paternal
- With imprinted genes we inherit only one working copy (either maternal or paternal)
- The other copy (imprinted copy) is permanently silenced epigenetically by methylation.
- The epigenetic tags on imprinted genes usually stay put for the life of the organism.
However, they are reset during egg and sperm formation. Certain genes are always silenced in the egg and others are always silenced in the sperm. - There are at least 80 imprinted genes in humans and mice
The genetic conflict hypothesis
Attempts to explain why many imprinted genes are involved in growth and metabolism.
* Males can generally father multiple offspring with multiple partners simultaneously at a low cost of personal resources, so they prefer bigger offsprings to ensure survival.
* Females can only produce one set of offspring at a time and requires a greater cost of resources, so they prefer smaller offspring.
Therefore:
* Paternal imprinting favours the production of larger offspring.
* Maternal imprinting favours smaller offspring.
* Imprinting aims to regulate certain genes keep a balance between the costly reproduction process (female) and the desired effectiveness of reproduction (male).
Epigenetics in plants
Determine the color of flowers, number of petals, & plant flowering
* Modifications include DNA methylation, histone modifications, and the production of microRNAs (miRNAs)
Ex: Epigenetics changes in plant DNA, to control a certain set of genes/ alter gene expression pattern, ensure the production of flowers even when plants are growing under adverse conditions.
Conclusion
- Epigenetics is the modification of the chromatin (the assembly between DNA and histones) which can be inherited. The mechanisms are independent of the DNA sequence itself.
- Different histone modifications clearly label the different regions of the genome – active regions have different kinds of modifications to the inactive regions (ex. active vs inactive enhancers or facultative vs constitutive heterochromatin) – this gives information about gene expression
- Epigenetics can be related to phenotypes, can be influenced/impaired by environmental factors which can further result in diseases.
- Imprinting – permanent repression of 1 copy of the allele of a gene
