Flashcards in Lecture 14 - Epigenetics Inheritance and Imprinting Deck (61):
What is a big example of epigenetics?
Paternal lifestyle choices leading to obesity and T2D (eg: high fat diet) are passed on as beta cell dysfunction (aka glucose intolerance) to female progeny by passing on methylation patterns of 77 insulin and glucose metabolism genes
What is the classic definition of epigenetics?
Information that is passed from one generation to the next (either to daughter cells during division or from parent to offspring) but is NOT encoded in the primary DNA sequence
What is the epigenome?
Range of modifications to the genome (DNA) that ensure the stable transmission of gene expression patterns without changes to the DNA sequence
What are epigenetics disruptors?
Factors that influence our epigenetic inheritance patterns
What is genomic imprinting? Purpose?
The ability to mark a gene as coming from either the father or mother with different methylation patterns
To be able to only express one allele
What 4 diseases are associated with epimutations and genomic imprinting?
1. Beckwith-Wiedemann syndrome
2. Prader-Willi syndrome
3. Angelman syndrome
What is a transgenerational phenotype?
The effect of multigenerational exposure in subsequent generations (F3 and beyond)
In pregnant females, in what generations can environmental exposure cause epigenetic modifications? What is this called?
In the next two generations (F1 and F2) through the fetus and its germ line
In males, in what generations can environmental exposure cause epigenetic modifications?
Multigenerational exposure in males is limited to the F0 and F1 generations
What is the basic and main mechanism of epigenetics?
Methylation of cytosine in DNA to form 5-methyl cytosine
What is particular about cytosine methylation in vertebrates?
Confined to cytosines in a CG sequence
What is 5-methylcytosine comparable to?
Mix between T and U
Product of deamination of 5-methylcytosine?
How are methylation patterns retained during DNA replication?
Maintenance methyl transferases recognize methylation patterns on the parent strand and replicate it on the daughter strand following DNA replication
What are the 3 maintenance methyltransferases?
1. DNA methyltransferase 1 (DNMT 1)
2. DNA methyltransferase 3A (DNMT3A)
3. DNA methyltransferase 3B (DNMT3B)
What is another name for maintenance methyltransferases?
Methyl-directed methylating enzyme
How does DNA methylation affect gene expression? Explain how it works.
It contributes to mechanisms of stable gene REPRESSION because it provides binding sites for DNA methyl-binding proteins that will prevent the DNA from being accessed, thereby silencing it
How are repressive chromatin structures usually formed? 2 steps
1. Histone writer protein attracks histone readers
2. A de novo DNA methylase is attracted by the histone readers and methylates nearby cytosines in DNA
3. Methylated DNA is then bound by DNA methyl-binding proteins
Can histone modification patterns be inherited? How?
Histone writer enzymes are inherited and reproduced the pattern
What is the leaky gene hypothesis?
Under normal circumstances genes are upregulated due to some signal and when we want to downregulate it, we remove the gene activator or add a repressor (or both). This slows down gene expression, but it's not completely turned off, demonstrating the leaky behavior to the expression of these genes.
How can we completely turn a gene off instead of just down-regulating it?
What triggers DNA methylation?
Cell no longer produces activating transcription factors => gene regulatory proteins and transcription machinery dissociates from DNA => DNA methylation
Following the binding of DNA methyl binding proteins, how else is the DNA further silenced? 2 ways
1. Recruitment of chromatin remodeling complexes
2. Recruitment of histone deacetylases
By what fold can DNA methylation affect the rate of gene expression in different tissues?
1 million fold
In what organisms does genomic imprinting occur?
Does genomic imprinting affect all genes in mammals?
NOPE, only a few
Describe the steps of genomic imprinting from germ cell formation to offspring. What can this cause?
1. Genomic imprinting is removed from somatic cells in germ cells, followed by meiosis
2. Female genes NOT imprinted, males genes are through methylation
=> Different imprinting patterns can cause phenotypic differences in the progeny even if they carry exactly the same DNA sequences of the two gene alleles
What provides an important exception to classical genetic behavior?
Describe genomic DNA methylation in embryonic development. 3 steps
1. Following fertilization, first the paternal genome is ACTIVELY demethylated prior to the first cleavage division
2. Maternal demethylation occurs through a PASSIVE mechanism after several cleavage divisions
3. De novo methylation occurs in the inner cell mass (ICM) cells, which later differentiate into the embryo
What are 2 exceptions to the classic genomic DNA methylation mechanisms in embryonic development?
1. Imprinted genes
2. Repetitive elements
What is an example of an imprinted gene?
Igf2 = insulin like growth factor 2
What is the genetic conflict hypothesis?
Males and females have different goals when it comes to the type of offspring they want to generate:
- Males want to generate big, strong, capable offspring that can compete for resources and pass genes on for generations
- Females want to generate offspring that are not too big and strong that delivering them would kill her and she would no longer be able to generate further generations
What is a solution to the genetic conflict hypothesis?
Explain how genomic imprinting can solve the genetic conflict hypothesis by using the Igf2 example.
The genes for Igf2 and its receptor are both imprinted and therefore cancel each other out to regulate the size of the offspring:
- Paternal genes: Igf2 ON (because insulator element is methylated) and receptor OFF
- Materal genes: Igf2 OFF and receptor ON
However, changing the imprint on one copy of the gene has dramatic effects on the size of the offspring:
- Deleting mother's Igf2 receptor gene turns the paternal imprinted silent allele causing large offspring
- Deleting the father's Igf2 gene turns the maternal imprinted silent allele on causing dwarf offspring because it contains an insulator element that blocks Igf2 expression
How does deleting an allele from one parent affect the expression of the alleles in the other for imprinted genes?
It activates the imprinted silent allele in the other parent
What were the first 2 imprinted genetic disorders to be described in humans?
1. Prader Willi syndrome
2. Angelman syndrome
What do PWS and Angelman's syndromes result from?
Chromosome deletion at 15q11-q13
- PWS: paternal deletion (genes SNRPN and NDN are not methylated): genes SNRPN and NDN not expressed
- Angelman's: maternal deletion (gene UBE3A not methylated): gene UBE3A not expressed
What are the 3 symptoms of PWS?
What are the 3 symptoms of Angelman syndrom?
3. Perpetually smiling facial expression
What is Beckwith-Wiedemann syndrome?
Overgrowth disorder usually present at birth characterized by an increased risk of childhood cancer and certain congenital features
What is NOEY2?
Paternally expressed imprinted gene located on chromosome 1 in humans
What is a loss of NOEY2 linked to? Why?
Risk of ovarian and breast cancers because it functions as a ras-like tumor suppressor gene in breast and ovarian tissue
What is it called when a child inherit both chromosomes from 1 parent?
What is a specific example of an alteration in gene expression due to high fat diet in father rats?
Il13ra2 (part of Jak-STAT signaling pathway) gene's methylation was decreased, thereby increasing gene expression
How can prenatal protein undernourishment in rats affect gene expression?
The offspring of rats fed a protein-restricted diet show:
1. Under-methylation (higher gene expression) of certain genes involved with fatty acid breakdown (resulting in these rats being ketotic)
2. Increased glucocorticoid expression (resulting in stimulation of gluconeogenesis and higher blood glucose levels).
These effects were prevented by supplementation of the maternal diet with folate
What is the effect of neonatal leptin treatment on metabolic programming caused by maternal undernutrition in the rat?
Female rats were subjected in utero to maternal undernutrition and then treated with saline or leptin between days 3 and 13 of life, and fed a high fat diet after having been weaned.
Neonatal leptin treatment prevented the increased susceptibility to diet-induced obesity associated with a high-fat diet after maternal undernutrition.
How will environmental cues during development in utero predicting a nutritionally sparse environment determine the adult phenotype? How can postnatal cues worsen the situation?
These cues will cause a shift in the trajectory of structural and functional development toward a phenotype matched to that environment: phenotype will have a reduced capacity to cope with a nutritionally rich environment later in life, increasing the risk of metabolic disease.
Postnatal cues, such as childhood overnutrition leading to compensatory growth, could further shift the positioning of the adult phenotype, exacerbating the mismatch between phenotype and environment.
What are some DNA methylation and gene expression differences in children conceived in vitro vs in vivo? What does this suggest?
Children conceived in vitro have a greater risk of low-birth weight, major and minor birth defects, and rare disorders involving imprinted genes.
This suggests that epigenetic changes may be associated with assisted reproduction (lower methylation in placenta and higher methylation in cord blood)
How do the promotor regions of constitutive vs inducible genes differ? What do these mean?
Some housekeeping genes have CG rich regions in the promoter near the CCAAT box = "CG islands"
Methylated cytosines in CG islands are often replaced by thymine due to deamination. Therefore, housekeeping genes that still have these CG islands represent genes that have not typically been silenced through DNA cytosine methylation over millions of years of evolution
Is the deamination of 5' methyl cytosine to thymine recognized for repair?
Other than methylation, what are 2 other epigenetic signals?
1. Trans signals: transcription factors are transmitted by partitioning of the cytosol during cell division and maintained by feedback loops
2. Cis signals: molecular signatures physically associated with the DNA and inherited via chromosome segregation during cell division
What 4 mechanisms can produce an epigenetic form of inheritance in an organism?
1. Positive feedback of protein synthesis
2. Histone modifications
3. DNA methylation
4. Protein aggregation state (prions)
What is responsible for phenotypical differences in identical twins?
What is X chromosome inactivation? Purpose? How is this inactivation achieved? At what stage in embryo development does this happen? When do they go back to both being active?
One of the two X chromosomes in the cells of females is inactivated by extreme condensation. The purpose of X-chromosome inactivation is dosage compensation, or preservation of the cells from an excess of X-chromosomal gene products.
In the inactivated X chromosome, the XIST gene is unmethylated and expressed from the X-inactivation Center (XIC) locus (producing a long uncoding RNA that wraps around the X chromosome), whereas in the active X chromosome, this gene is methylated and silent.
This happens when the inner cell mass differentiates into the epiblast and hypoblast: permanent in somatic cells and back to normal in germ cells after the first mitotic division
What is a Barr body?
Condensed X chromosome
Which X chromosome is silenced during X chromosome inactivation? What does this create?
Randomly selected each time = mosaic of clonal cells with either Xp or Xm silenced
What does the mosaic of clonal X cells cause in cats?
Tortoise hair, meaning the cat is female
How is dosage compensation achieved in drosophilia?
Genes on single X present in males are expressed at 2-fold higher levels
How is dosage compensation achieved in nematodes?
Genes on the 2 X chromosomes (hermaphrodites) are expressed at half the levels of the male single X chromosome
What do ALL dosage compensation mechanisms involve?
Structural alterations over the entire X chromosome