Imprinting

Question 1

Genomic Imprinting

Answer 1

Marks certain chroms, sub chrom domains or loci in differential expression of parental alleles in somatic tissues

Question 2

Imprinted genes

Answer 2

Inherit only 1 working copy

One copy is epigenetically silenced

Silencing through acetyl & methyl grps to DNA or histones during egg/sperm formation

Question 3

Mechanism

Answer 3

Imprinted genes controlled by cis acting reg elements- ICRs

Have parental specific epigenetic modifications like DNA CH3-

Methylated by de novo DNA CH3transferases during germline dev

Question 4

Mech

Answer 4

Many imprinted genes found in clusters & have 2 major mech:

• CTCF dep insulators
• long noncoding RNAs

Unclustered imprinted genes are reg by germline CH3-

Question 5

Insulator

Answer 5

genetic boundary element that blocks the interaction between enhancers and promoters.

The need for them arises where two adjacent genes on a chromosome have very different transcription patterns, and it is critical that the inducing or repressing mechanisms of one do not interfere with the neighboring gene.

Mediated by protein CTCF

Question 6

Silencing by CpG island or promotor CH3-

Answer 6

CTCF- red disk

bind to unCH3- allele & block access of upstream promoter to downstream enhancer (in green)

Causes transcriptional repression of upstream gene

Question 7

Antisense transcripts & CpG island methylation

Answer 7

Diff CH3- results in diff binding of silencing factors

This represses promoter in cis

Question 8

Diff pronuclei experiments

Answer 8

Gynogenetic- 2 female pronuke

androgenetic- 2 male pronuke

Question 9

Natural pronuke

Answer 9

ovarian teratoma 46 XX: benign tumor

Hydatidiform mole- 46 XX, hyperplasia of trophoblast no embryo

• Choriocarcinoma- in 50% of cases

Question 10

Imprinted Genes

Answer 10

Question 11

Through Experiments w/ pronuke

Answer 11

dev in absence of sperm derived genome= good dev of embryo but failed trophoblast dev

dev in absence of egg derived genome= failed dev of embryo proper but exuberant trophoblast growth

Question 12

IGF-2 example

Answer 12

Deleting mother’s IGF2 R & father’s IGF2 gene produces normal sized offspring (genetic conflict hypothesis)

Delete Mother’s IGF2 R produces overly large offspring

Delete father’s IGF2 gene produces dwarf offspring

*considering mom’s IGF2 R is on & dad’s IGF2 is on

Question 13

Hydatidiform Mole

Answer 13

trophoblast tissue burrow into uterus

placenta has fluid filled cysts from chorionic villi

Complete= 46 chrom strictly from paternal origin. Empty ovum by 2 sperm or 1 endoreduplication sperm

partial= 69 chrom triploidy, where 46 from father & 23 from mom

• due to dispermy in endoreduplication
• 69 XXY OR 69 XXX
• fetus there but doesn’t survive

Question 14

Beckwith Wiedeman Syndrome

Answer 14

overgrowth

congenital malformations

perdisposition to embryonic neoplasia

sporatically or epigenetic changes @ chrom 11 diff methylated regions

Question 15

BWS

Answer 15

IGF2 causes growth of embryo

IGF2R internalizes IGF2 & inhibits cell growth

IGF2 gene from mom are turned off so IGF2R is on

IGF2R gene from dad is off so IGF2 is on

Father trying to make fetus grow & mother trying to inhibit fetus growth

Question 16

Imprinting of IGF2R gene

Answer 16

Female methylates 3’ promoter while 5’ promoter unmethylated

Mother’s chrom generates sense transcript

Father’s chrom generates antisense transcript

Net effect= down reg IGF2R gene to counter growth of IGF2

Question 17

IGF2 gene imprinting

Answer 17

Female doesn’t methylate CTCF (insulator) binding site

CTCF can bind & block 3’ enhancers so only H19 transcription occurs not IGF2

For male- imprinting center is methylated so CTCF can’t bind

Enhancer of 3’ H19 can upregulate IGF2 transcription

More IGF2 is available= fetus stimulated to grow

Question 18

Prader Willi Syndrome

Answer 18

reduced motor f

obesity

mental def

from father

Question 19

Angelman syndrome

Answer 19

hyperactivity

unusual seizures

repetitive m. movements

mental def

from mother

Question 20

Maternal Chrom 15

Answer 20

DNA cytosine CH3

H3 tail CH3- @ lys 9

recrutiment histone deacetylating enz

deacetylated histones

Silencing asUBE3A permits expression of UBE3A from maternally inherited chrom

Question 21

Paternal Chrom 15

Answer 21

no DNA cytosine methylation

H3 & H4 tails are lys 4 methyl & acetylated

Recruit histone acetyltransferase (HAT)

Transcriptionally active chromatin

virtual deletion of some genes like UBE3A & ATP10C

Question 22

Results

Answer 22

lack of expression UBE3A- no EA6P protein that transforms small ubiquitin molecs to certain proteins to target their degradation

• AS
• paternally silenced

lack of SNRNP- small nuclear ribonucleoprotein that controls gene splicing necessary for syn of critical proteins in brain

• PWS
• maternally silenced

Question 23

Modifications

Answer 23

DNA methy= repress

histone methylation= repression & activation

histone demthyl= “

histone acetylation= active

deacetyl= repress

histone phosphorylation= active/repress

histone ubiq= repression/activation

histone sumoylation= repression

Question 24

Imprinting

Answer 24

Question 25

Imprinted Maternally expressed phenotype

Answer 25

Phenotype expressed= When mutant allele is inherited from mother

Mutant imprinted alleles can be masked when paternally inherited but clincally re-appear in 1/2 of children of carrier daughters

Silenced mutation if passed on to children- then its important