Lecture 5 Flashcards
What is genomic imprinting?
A form of epigenetic regulation that results in mono-allelic expression in a parent-of-origin-dependent manner
How imprinted genes are there? Where in the genome are they found?
How are they regulated?
~90 imprinted genes
Often found in large clusters
Regulated by an Imprinting control region (ICR) for each cluster, as well as non-coding RNAs and differential DNA methylation
What is imprinting established?
During gametogenesis and not removed during global erasure after fertilisation
Which protein has been implicated in protecting these genes?
PGC7/Stella
As seen in protecting maternal non-imprinted genes from active de-methylation
When is the methylation pattern of the primordial germ cell precursors erased?
Whilst migrating through the embryo to the gonad’s
When is parental imprinting put down?
Before birth and maintained through the meiotic divisions that give rise to sperm cells
When is maternal imprinting put down?
Post birth during the oocyte maturation
What happens if both pronuclei are from the same sex?
Nuclear transfer of pronuclei to create all combinations showed that pronuclei from the same sex could not create a fully formed embryo or extra-embryonic tissue
Two female nuclei= trophoblast undergrowth, and small embryo
Two male nuclei= trophoblast overgrowth, and deformed embryo
How is H19-Igf2 imprinted differently between maternal and paternal?
What is each protein for?
Maternal chromosome has active H19 and inactive Igf2, and the inverse in paternal. H19 is a non-coding RNA and Igf2 encodes a protein that promotes embryonic and placenta growth.
What causes the difference in imprinted H19-Igf2 between maternal and paternal?
The two genes are separated by an imprinting control region (ICR). In females the ICR is not methylated and bound by CTCF (an insulator), blocking enhancers down stream from causing Igf2 expression and instead H19 is expressed . In males the ICR is methylated and CTCF cannot bind so enhancer cause expression of Igf2.
What was shown about H19-Igf2 in mice experiments?
Igf2 mutant female crossed with normal male= normal offspring
Normal female crossed with Igf2 male= small off-spring
What pair of imprinting disorders are associated with the H19-Igf2 cluster?
Beckwith-Wiedemann (BWS) and Silver-Russel (SRS) syndrome
What epigenetically causes BWS and SRS and what are the phenotypes?
BWS= Gain of methylation on the maternal ICR, and Igf2 is expressed from both alleles. Causes overgrowth disease SRS= Loss of DNA methylation of paternal ICR, and H19 expressed in both alleles. Causes growth retardation
What controls the Igf2R-Air cluster?
Anti-sense transcription and differential DNA methylation
Which is expressed in which sex’s gamete?
IGF2R in maternal and Air in Paternal
How is expression of the Igf2R-Air cluster controlled between the sexes?
In maternal, methylation of Air ICR switches off AIR and allows Igf2R
In paternal, lack of methylation of Air ICR allow its expression, which turns off Igf2R, due to Air being antisense to Igf2R
What is the common pattern in effect on growth of alleles from the sexes?
Maternal allele is trying to suppress growth and paternal allele is trying to encourage growth