Lecture 7: Epigenetics and disease Flashcards
(41 cards)
What are three common characteristics of Angelman Syndrome?
- Developmental delay
- Speech impediment
- jerky movements, hand flapping
- happy disposition
- microcephaly
- seizures
7 abnormal EEG (abnormal brain activity)
What are three common characteristics of Prader-Willi Syndrome?
- hypotonia (low muscle tone)
- poor feeding in infancy
- insatiable appetite later in life
- obesity
- short stature
- compulsive behaviour
- strabismus
- hypogonadism/poor sexual development
What is the deletion commonly responsible for both Angelman and Prader-Willi syndrome?
deletion of up to 6 Mbp on chromosome 15q11.2 - q13.1
(for Angelman and Prader-Willi Syndrome) Why can a deletion occur within chromosome 15 and what are the two types of deletions that can occur?
Repeat sequences in break points can undergo aberrant meiotic recombination resulting in type I or type II deletions:
Type I = deletion between break point 1 and break point 3.
Type II = deletion between break point 2 and break point 3.
What explains the difference in PWS and AS despite being caused by the same chromosomal deletion?
Genomic imprinting
What is genomic imprinting?
An epigenetic trait in which the expression of genes from one chromosome is silenced but there is no change to the DNA sequence
What does genomic imprinting mean for the 15q11.2-13.1 region?
Some genes in this region are expressed only on the paternal chromosome (silenced on the maternal chromosome) and some genes are only expressed on the maternal chromosome (silenced on the paternal chromosome)
- this means in a usual situation, an individual will still express all genes as they have inherited one of each chromosome from their mother and father
How does genomic imprinting relate to an individual having Prader-Willi syndrome?
- Type I deletion in paternal chromosome means that the individual won’t express any of the paternal genes in this region since they have been deleted on the paternal chromosome and imprinted on the maternal chromosome
How does genomic imprinting relate to an individual having Angelman Syndrome?
- Type I deletion in maternal chromosome means that the individual won’t express any of the maternal genes in this region since they have been deleted on the maternal chromosome and imprinted on the paternal chromosome
What is genomic imprinting an example of?
An epigenetic trait
What is the definition of an epigenetic trait?
a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence
What are the three mechanisms involved in epigenetic modification of gene expression?
- methylation of cytosine residues in DNA causing it to be sequestered into heterochromatin
- Histone modifications
- Regulation of lncRNA (important in X-chromosome inactivation)
What epigenetic modification is responsible for genomic imprinting?
methylation of cytosine bases at CpG sites in differentially methylated regions (DMRs)
What are the two mammalian methyltransferases responsible for genomic imprinting?
- de novo methyltransferases = fully unmethylated DNA is methylated at the 5’ cytosine of CpG site on one strand (hemimethylated)
- maintenance methyltransferases = recognises heavily methylated DNA and adds methyl group to the CpG site of the opposite strand.
What happens when epigenetic methylation occurs in embryo and somatic cells?
the resulting gametes will have the same methylation pattern
(E.g. all oocytes/sperm will have the same methylation pattern as the maternal/paternal chromosomes)
These genomic imprints persist in the zygote somatic cells
True or false: If a chromosome of paternal origin is packaged into an oocyte, it will still have a methylation pattern that matches the paternal chromosome?
False: no, the methylation pattern will be imprinted to match that of the maternal chromosome since it is of maternal origin when passed on next.
(if this doesn’t make sense, covered on slide 12 of lecture 7)
Where does genomic imprinting occur?
Paternal (established in prospermatogonia in testes of foetus)
Maternal (established during oocyte maturation in meiosis)
Why is genomic imprinting removed in primordial germ cells?
maternal and paternal imprints are removed in primordial germ cells so that the correct imprinting can be re-established in the gametes based on the biological sex of the individual (E.g. if the individual is female, the maternal and paternal imprints will be removed in the germ cells and the gametes will have have maternal imprinting, since all these chromosomes will have come from the maternal side)
(if this doesn’t make sense, covered on slide 12/13 of lecture 7)
How are the PWS genes imprinted on the maternal chromosome 15?
- imprinting centre (IC) of maternal chromosome is methylated sequestering adjacent region into heterochromatin
- blocks the transcription of PWS genes flanking the IC site silencing them
- Angelman syndrome genes (ATP10A and UBE3A) still active
How does PWS occur and what causes PWS?
Occurs when there is a deletion of 15q11.2-13.1 in paternal chromosome and maternal chromosome is silenced.
Cause:
particular deletions implicate disruption to the cluster of small nucleolar RNAs (snoRNAs) located in introns of SNHG14 (small nuclear host gene 14) transcript
How does the SNHG14 transcript differ in the brain?
highest expression levels and longest transcript in the brain
How does the SNHG14 transcript differ in non-neuronal cells?
Transcript terminates after the SNORD116 locus
How are the AS genes imprinted on the paternal chromosome in non-neuronal cells?
- imprinting centre (IC) of the paternal chromosome is unmethylated and gene expression is activated
- SNHG14 transcript terminates after SNORD116 locus
- most PWS genes are expressed as well as AS genes including UBE3A
Which snoRNA cluster is most important in PWS? and how do they know this?
SNORD116 cluster of snoRNAs
They know this because there are some patients with PWS that have rare small deletions that disrupt SNORD116 and still have the disease (so this must be an important gene in disease implication)
