epigenetics: genomic imprinting. genomic imprinting preferential expression (or repression) of one...

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.