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l3 epigenetics > Genomic imprinting > Flashcards

Genomic imprinting Flashcards

1
Q

What is genomic imprinting? (2)

A
  • Parent of origin specific gene expression in mammals
  • Some mutant phenotypes are only expressed in progeny when the mutation is transmitted from a particular parent
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2
Q

What is an example of genomic imprinting? (5)

A
  • Thp mutation leads to viable progeny when transmitted from father
  • Thp mutation leads to inviability when transmitted from mother, causes increased body size
  • These progeny are genotypically identical but one is normal and one is inviable
  • Not linked to progeny sex because Thp mutation is autosomal (chromosome 17) and progeny can be male or female
  • Implies that mammalian male and female gametes have distinct developmental potential
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3
Q

How are embryos with 2 male/2 female pronuclei constructed? (5)

A
  • Maternal pronucleus is smaller than paternal pronucleus
  • Remove paternal pronucleus from host mouse zygote and replace with a second maternal pronucleus from a second donor zygote to create a diploid gynogenetic embryo
  • Do the same with paternal pronuclei to create a diploid androgenetic embryo
  • Embryos with 2 male/2 female pronuclei are lethal
  • Male AND female pronuclei are required for normal embryonic development
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4
Q

Why do diploid androgenetic embryos fail to develop to term?

A

Development of embryo and yolk sac is very impaired but trophoblast develops to normal size

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5
Q

Why do diploid gynogenetic embryos fail to develop to term?

A

Development of embryo is relatively normal but yolk sac and trophoblast development are both severely impaired

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6
Q

What are the paternally expressed imprinted genes? (2)

A
  • Embryonic growth-promoting genes
  • Igf2, Peg1, Peg3, Rasgfr1, Dlk1
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7
Q

What are the maternally expressed imprinted genes? (2)

A
  • Embryonic growth-repressing genes
  • Igf2r, Gnas, Cdkkn1c, Grb10
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8
Q

What is the parental conflict hypothesis? (3)

A
  • Embryos of placental mammals depend on the maternal environment for nutrition during gestation
  • The paternal genome optimises its fitness by maximising the embryo’s use of maternal nutritional resources i.e. by paternal expression of growth promoters
  • The maternal genome optimises its fitness by limiting exploitation of maternal nutritional resources by the embryo i.e. by maternal expression of growth repressors
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9
Q

What are the key characteristics of genomic imprinting in mammals? (4)

A
  • DNA methylation is the only modification that functions as the molecular imprint, histone modification plays a minor role
  • The 7 clusters each have a differentially methylated region (DMR), a DNA sequence with a parent-of-origin specific DNA methylation imprint
  • Many clusters of imprinted genes are controlled by gametic DMRs that function as regulatory elements for the cluster overall called imprint control elements (ICEs)
  • Most of the 7 clusters contain a combination of protein coding and non-coding genes
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10
Q

How many of the 7 clusters have a maternal methylation imprint laid down in the oocyte?

A

5/7 - Igf2r, Kcnq1, Gnas, Grb10

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11
Q

How many of the 7 clusters have a paternal methylation imprint laid down in the sperm?

A

2/7 - Igf2, Dlk1

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12
Q

What are gametic DMRs?

A

Methylation imprints laid down in the oocyte/sperm

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13
Q

How many imprinted genes are there? (3)

A
  • Around 150 imprinted genes identified
  • 80% of these are clustered in 16 genomic regions containing 2 or more genes
  • 7 clusters are well characterised and contain 3-12 imprinted genes
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14
Q

How is genomic imprinting affected by the genome wide DNA demethylation after fertilisation? (2)

A
  • Imprinted DMRs are a special subset of DMRs which persist in SOMATIC tissues on paternal/maternal chromosomes throughout embryogenesis and into adult life (don’t lose the imprint)
  • Genomic imprints ARE erased in the primordial GERM cells of the early embryo before sex determination and a new imprint is created in gametes according to the chromosomal sex of the embryo
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15
Q

What machinery is involved with erasure and creation of new imprints in gametes? (3)

A
  • Erasure: TET demethylases and/or passive demethylation
  • Acquisition: DNMT3A, DNMT3B de novo methyltransferases
  • Maintenance: DNMT1 maintenance methyltransferase
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16
Q

What is the T hairpin (Thp) mutation? (3)

A
  • Deletion (i.e. complete loss of function) on chromosome 17 (autosomal)
  • Imprinted gene is Igf2r
  • DNA methylation imprint is located in the second intron of Igf2r
17
Q

Which combination of Thp mutation/wt results in normal progeny? (2)

A
  • Thp mutation on paternal chromosome 17
  • Wildtype on maternal chromosome 17
18
Q

Which combination of Thp mutation/wt results in inviable progeny? (2)

A
  • Thp mutation on maternal chromosome 17
  • Wildtype on paternal chromosome 17
19
Q

What is the function of IGF2R? (3)

A
  • IGF2R (receptor) is a scavenges IGF2 and targets IGF2 to lysosomes
  • Prevents IGF2 binding to IGF1 receptor and causing growth-promoting effects of IGF2 signalling
  • Therefore IGF2R is a growth repressor
20
Q

Why does embryo with maternally-derived Thp mutation show increased body size? (3)

A
  • Loss of function of IGF2R so overactivation of IGF2 growth-promoting signalling
  • Paternal copy isn’t doing growth suppression (silenced)
  • When Thp mutation is paternally-derived, the maternal IGF2R copy is able to repress growth as normal
21
Q

How does maternal/paternal differential methylation of Igf2r work? (5)

A
  • Counterintuitive: maternal G-DMR is methylated and Igf2r is expressed, paternal G-DMR is unmethylated and Igf2r is silenced
  • The methylation of the Igf2r G-DMR prevents transcription of the overlapping 108kb long ncRNA Airn RNA on the maternal chromosome
  • Airn transcript attenuates Igf2r expression therefore silencing Airn de-represses Igf2r on the maternal chromosome
  • No paternal methylation so Airn is expressed and silences Igf2r
  • Igf2r G-DMR is an imprinting control region (ICE)
22
Q

How are Igf2r and Igf imprinting linked? (3)

A
  • Complementary imprinting
  • Maternal Igf2r is methylated which causes Airn repression and Igf2r expression
  • Paternal Igf2 is methylated which prevents CTCF binding so a downstream enhancer can activate Igf2 transcription
23
Q

What is CTCF?

A

Insulator element across which transcription factors can’t function

24
Q

Why isn’t Igf2 maternally expressed? (2)

A
  • Maternal Igf2 ICE is unmethylated which allows it to bind CTCF
  • CTCF prevents Igf2 being activated by a downstream enhancer which instead activates expression of H19 long ncRNA

l3 epigenetics (15 decks)

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