epigenetics: genomic imprinting. genomic imprinting preferential expression (or repression) of one...
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Epigenetics:Genomic imprinting
Genomic Imprinting• Preferential expression (or repression) of one parental allele• Epigenetic modification mechanism (CpG methylation)
paternal
maternal
imprinted gene autosomal gene
DNA methylation
Promoterw/ no DNAMethylation
w/ DNA Methylation
Genomic Imprinting• Eutherian-specific • Dosage control of genes with
fetal growth functions
(Igf2 – fetal growth factor
Igf2r – fetal growth suppressor)
maternal-caring behabiors
(Peg3 – female KO mice
---> bad mothers
---> milk let down, nest building)
170-200 mya
Monotreme (Platypus)
Marsupial (Kangaroo)
Placental Mammal (Gorilla)
130 mya
Discoveries of genomic imprinting
Mammals need two parental genome
Nuclear transfer experiments at mid 1980’sdemonstrated this notion.(Azim Surani et al)
Other translocation mutants breeding(Bruce Cattanach et al)
Early 1990 identified several genes that are Imprinted in a parental allele-specific manner(Igf2, H19 by Tilghman et al; Igf2r by Barlow et al)
Mouse model for genomic imprinting
Uni-parental disomies
Deletion of one allele
Polymorphisms (SNPs)
Ontogeny of genomic imprinting
Imprinting signals (eg DNA methylationand histone modification) are established during gametogenesis.
These signals are maintained throughoutthe life time of somatic cells.
In the germ cells of the first generation,another round of imprints resetting occurs forthe following 2nd generation.
Functions of imprinted genes
Fetal growth rate
Maternal-caring behavior
Features of imprinted gene clusters
• Imprinted genes are clustered in chromosomal regions.
• Imprinted genes with both parental specificity are co-localized in a given domain.
• Imprinted gene clusters tend to have long non-coding mRNA genes, and these mRNAs play significant roles for imprinting control.
- Provide several paradigms for long distance transcriptional regulation in mammalian systems.
Features of imprinted gene clusters
Clustering of imprinted genes:one lnc (long non-coding) mRNA + several protein-coding mRNA
Imprinting Control Regions(Gametic DMR- Differentially Methylated
Region)
Two known mechanisms for imprinting
Insulator model (H19/Igf2 – CTCF)
Silencing by ncRNA (Igf2r –Airn)
Unsolved questions (???)
• How ICRs (gametic DMRs) obtain DNA methylation during gametogenesis
• How these DMRs are maintained throughout development, in particular early embryogenesis.
• Each imprinted cluster has different mechanisms for allele-specific expression in somatic cells, which requires more thorough analyses.