- Small number of genes are marked on their parental allele
- Only one parental allele is expressed
- 1980: pronuclear transplantation experiments demonstrated that mammalian development requires contribution from both parents
- Maternal uniparental embryos were exclusively embryonic tissues
- Paternal uniparental embryos developed into extra-embryonic structures only
- Engineering of offspring dome through combination of nuclei from nongrowing and fully grown oocytes with mutations in 2 different imprinted loci
- Resulting bimaternal offspring had normal imprinted gene expression
- Some methods used to identify imprinted genes:
- Molecular characterization
- Gene targeting experiments
- Genome wide studies – more popular once sequencing of the whole genome possible
- Igf2r: insulin-like growth factor type 2 receptor, first of 3 imprinted genes reported in 1991
- H19 gene encodes a ncRNA, maternal-specific expression (identified via SNPs)
- To date, ~100 imprinted genes have been found in mammals
- ICRs: imprinting control regions, shows parent-of-origin specific epigenetic modifications that are set up in the germline
- Many imprinted genes are dosage sensitive, with over/under expression resulting in consequences
- e.g. prenatal growth control, brain function, postnatal energy homeostasis
- Conditions that result from faulty imprinting:
- Prader-Willi syndrome: loss of expression of SNRPN implicated, but contribution unknown
- Angelman syndrome: caused by the absence of UBE3A transcript expressed from maternal chromosome
- Beckwith-Wiedemann syndrome:
- Silver-Russell syndrome:
- Placenta and the brain are sites of widespread imprinted gene expression
- Absence of Igf2r causes impaired nutrient transport to the fetus
- Peg10, Rtl1 are imprinted genes required for placental development, originated from retrotransposons
- In the brain, imprinted genes are implicated in metabolic axes, behaviour, learning, maternal care
- G5a: gene expressed from the maternally inherited chromosome in the hypothalamus, controls melanocortin-mediated energy expenditure
- Peg1, Peg3 paternally expressed imprinted genes, strongly transcribed in brain, KO leads to decreased maternal care
Properties of the Imprinting Mechanism
4 important properties of the genomic imprinting process:
- The mark must be able to influence transcription
- It must be heritable in somatic lineages
- The mark is likely to be placed on the chromosomes when the paternal and maternal chromosomes are located in different nuclei
- Must be a mechanism of erasure so that paternally inherited chromosomes in the female germline can establish a new mark and vice versa