Imprinting in mammals Flashcards
What is genetic imprinting?
epigenetic phenomenon that causes genes to be expressed or not depending on whether they are inherited from the female or male parent
Maternal imprinting
gene from mother is transcriptionally silent
phenotype governed by paternal allele
Paternal imprinting
gene from father is transcriptionally silent
phenotype governed by maternal allele
What was the first evidence of genetic imprinting?
enucleated mice oocytes → control diploids + gynogenetic diploids implanted into mice
control → embryo viable
bimaternal → embryo inviable
Transmission of IGF-II mutation through male germline
heterozygous offpsring that are growth deficient
Transmission of IGF-II mutation through female germline
heterozygous offspring that are phenotypically normal
What did studies on IGF-II imprinting in mice show?
phenotype depends on the gamete contributing the mutation
paternal + maternal members of some autosomal gene pairs are functionally non-equivalent
How was it proven that only the paternal IGF-II allele was expressed?
nuclease protection + in situ hybridisation
How have bimaternal mice been generated?
stem cells extracted + cultured in medium that causes global DNA methylation
paternally imprinted loci deleted using CRIPSR
Bimaternal vs bipaternal reproduction in mice
bimaternal a lot easier to produce than paternal
paternal requires more steps + deletion of more imprinted genes required
paternal mice generated but died before adulthood
Examples of imprinting disorders
Beckwith-Weidemann syndrome
Prader-Willi syndrome
Angelman syndrome
Beckwith-Weidemann syndrome
large birth size
predisposition to tumours
Prader-Willi syndrome
obesity
behaviour + cognitive problems
deficiencies in sexual development
Angelman syndrome
developmental deficiencies
sleep disorders
seizures
happy disposition
What is BWS caused by?
abnormal regulation of genes on paternal 11p15.5 chromosome
leads to hypomethylation of ICR
What is ICR?
imprinting control region (1 and 2)
1 controls expression of IGF2 + H19 genes
2 controls expression of CDKN1C + KCNQ1
What is PWS caused by?
abnormal regulation of genes on paternal 15q11-q13 chromosome
maternal uniparental disomy
What is angelman syndrome caused by?
abnormal regulation of genes on maternal 15q11-13 chromosome
deletion of PW region
paternal uniparental disomy
What does uniparental disomy mean?
maternal- inheritance of both copies of a chromosome from the mother
paternal- both from father
underlies many imprinting disorders
What is the molecular basis of gene imprinting?
epigenetic regulation
methylation → gene silencing
acetylation → gene stimulation
Euchromatin
transcriptionally active
chromatin loosely coiled
HAT targets H3 tail
stimulates nucleosome accessibility
Heterochromatin
transcriptionally repressed
chromatin tightly coiled
KMTs methylate H3 tail
impairs nucleosome accessibility
What group of enzymes reverse histone acetylation?
histone deacetylases (HDACs)
