Imprinting Flashcards
What evidence is there that imprinting occurs?
If you insert two pro nuclei of the same sex into an egg this is lethal. All male egg has poor embryo development but normal post embryonic whilst all female are the opposite.
If you inherit two chromosomes from one parent this can cause disease. So the programming on parental chromosomes must be different.
Why might imprinting occur?
Imprinting results in the loss of the advantage of being diploid so why is it done?
Probably arose around 200MYA when we evolved viviparity and placentation.
Kinship theory - conflict between maternal DNA wanting to survive but paternal DNA wanted all the nutrients from the mother in the developing babies. e.g. in the placenta the IGF2 gene is expressed from paternal DNA whilst the recepor is expressed from maternal.
Also the coadaption theory - co evolution of maternal and paternal DNA to optimise foetal and maternal nurturing.
What are the characteristics of these imprinted regions?
Regions are located in clusters and there are about 150 clusters in humans. One allele is epxressed from one parent and the other is turned off via epigenetic alterations. This imprinting in stable and inheritable but reversible in germ-line.
Describe the imprinting that occurs at 11p15 from ICR1
ICR1 is methylated in the paternal chromsome but not the maternal. The paternal chromosome has differing levels of methylation in sperm vs pre implantation so it is also known as the DMR.
Upstream of the ICR1 is H19 - this is a non coding RNA that is expressed from the maternal allele and regulates IGF2 expression. Downstream of the ICR1 is the IGF2 gene which is expressed from paternal allele. These both share an downstream endoderm enhancer.
ICR1 is a chromatin binding element containing binding sites for CTCF. This binding is methylation sensitive. In the maternal allele there is no methylation at ICR1 and so CTFC binds and so prevents DNA from looping and so the enhancer can only regulate H19, the paternal allele is opposite.
DNMT1 KO = always maternal expression
How do germ lines reprogramme to be maternal or paternal?
In zygote the differing patterns of methylation must escape the normal wave if demethylation that occurs to create the pool of pluripotent stem cells that forms an embryo.
To convert germline from somatic methylation to sex specific female uses DNMT3L to establish a de novo imprint. H3K4me3 would normally block this so some demethylation must be required before.
In the male the piRNA pathway is used and also histones are hypoacetylated during spermatogenesis. DNMT1 and H3 methyltransferases are essential.
Mechanism of recognition is unknown but probably relies on histone modification.
Describe Beckwith-Weidermann and Silver Russel Syndrome?
Both disease at the 11p15 locus
BBS - congenital overgrowth syndrome and increase susceptibility to cancers. 80% of cases involve an imprinting defect. 5-10% have hypermethylation at ICR1 so there is a double dose of IGF2. 50% have hypomethylation at ICR2, 20-25% receive two paternal alleles and 5-10% have a LOF mutation in CDKN1C.
SRS - severe intrauterine and postnatal growth retardation due to opposite imprinting to BBS. 40-60% have hypomethylated ICR1.
Describe the methylation that occurs at ICR2 of 11p15
ICR2 normally hypermethylated in maternal allele. This is inside of the KCNQ1 gene (K+ channel), upstream of this is the CDKN1C gene which prevents mitosis to regulate tissue growth.
In paternal allele KCNQ10T RNA is produced which represses both genes. In maternal allele this is not produced and so both genes are expressed.
Describe the Angelman syndrome and Prader-Willi syndrome
Area of interest is 15q11-13
Angelman Syndrome = ataxia, intellectual disability and happy. 70% due to deletion on maternal chromosome, 2% due to inheriting two paternal chromsomes, 20% due to a gene mutation and 5% from an imprinting mutation that results in no reset of imprinting in the mother and so gives a paternally imprinted gene from her father.
Prader Willi syndrome - hyperphagia, obesity and intellectual disability. 70% are due to deletions on paternal chromosome, 25% due to inheriting two maternal chromosomes and 5% due to imprinting mutations that result in no reset of imprinting in the father and so gives a maternally imprinted gene from his mother.
PWS = no paternal expression AS = no maternal expression
Describe the imprinting that occurs at 15q11-13
This contains one ICR, with two sub regions, the AS ICR and the PWS ICR (which coincides with the enhancer of the SNURF/SNRPN gene). In the maternal chromosome the ICR is hypermethylated. This results in expression of only two maternal genes - UBE3A and ATP10C, this hypermethylation prevents the expression of the SNURF/SNRPN gene as well.
In the paternal chromosome the ICR is hypomethylated. As a result 4 genes are expressed including a long antisense RNA - UBE3A-AS. This modulates alternative splicing via snoRNAs.
Microdeletions of the two ICR mean no sex specific methylation can occur and can result in a parent giving a chromosome that has no change in imprinting.
