Gene imprinting

Question 1

Gene imprinting ?

Answer 1

phenomenon by which certain genes are expressed in a
parent-of-origin-specific manner

Question 1

Which vertabrates have imprinted genes?

Answer 1

Modern mammals aka marsupials and eutherians (plants and fungi also have it tho)

Question 2

Waves of demethylation during development?

Answer 2

One when germ cells are being formed (to introduce imprinting methylations in (paternal)sperm cells chromosomes
And another one after fertilization for non-imprinted genes.

Question 3

A difference in timing between paternal and maternal non-imprinted genes?

Answer 3

Paternal non-imprinted genes begin demethylation upon fertilization while for maternal non-imporinted genes demethylation begins only as the nuclei merge aka at the 1 cell stage

Question 4

Give 3 examples of imprinted gene clusters

Answer 4

Kcnq1, H19/Igf2, Snrpn

Question 5

For Kcnq1 which (paternal or maternal ) allele is methylated and which demethylated

Answer 5

paternal is demethylated, maternal methylated

Question 6

What is the mechanism behind imprinting in the Kcnq1 cluster

Answer 6

Kcnq1ot1( the paternal one) is demethyalted and thus expresses a lncRNA. This RNA recruits PRC2 and G9a which are writers that result in H3K27me3 and
H3K9me3 respectively => faculatative heterochromatin => genes in the cluster are not expressed while they are in the maternal chromosome

Question 7

Example of Kcnq1 cluster gene

Answer 7

Cyclin dependent Kinase 1c (CdK1), a tumor supressor

Question 8

What is the mechanism behind imprinting in the H19/Igf2 cluster

Answer 8

Paternal allele is methylated which prevents the Zinc finger CTCF from binding and insulating Igf2 (and Ins2) from enhancers resulting in their expression. As now these enhancer reach Igf2 and Ins2 they do not enhance the more closely located H19. (see figure from slides if you are still confused)

On the maternal allele where H19 is acitve it expresses lncRNA which serves as a decoy for Let-7 miRNAs, facilitates mRNA binding proteins and recruits MBD1, PRC2(H3K27me3) themselves leading to further inhibition.

Question 9

Beckwith-Wiedemann Syndrome characteristics

Answer 9

Fetal and post-natal overgrowth
Large tongue
Predisposition to embryonic/childhood tumours

Question 10

Causes of Beckwith-Wiedemann Syndrome

Answer 10

Loss of Impriting in the 11q5 region due to:
- loss of Cdk1nc (tumour suppressor, suppresses growth), H19, Kcnq1
- upregulation of Igf2 (oncogene, promotes growth)

these can be caused by epigenetic disruptions like hypomethylation of Kcnq1 or hypermethylation of Igf2

uniparental disomy can also result in the same effect (double the Igf2 => cancer)

Question 11

Prader Willi Syndrome?

Answer 11

deletion of paternal

Question 12

ICR?

Answer 12

Imprinting Control Reg

Question 13

On which chromosome region are Cdk1 and Igf2 located

Answer 13

11q15

Question 14

What is the reason for the intelectual deficiency in ppl with Angelman Syndrome

Answer 14

UBE3A which is only maternally imprinted only in the brain has been inhibited due to a lack of methylated PWS-IC. Other reason like UPD, or deletion of AS-ICR (which is crucial for the methylation of PWS_IC even though it itself is not methylatylated) can lead to the same effect.

Question 15

How are the two chromosomes differentially imprinted in the AS/PW ICR

Answer 15

The PW ICR is differentially methylated, methylated on the maternal and not on the paternal. Thus on the paternal chromosome multiple genes like Frat3 and Mkrn1 (no need to remember) are expressed as well as Snurf/Snrpn lncRNAs and snoRNAs (small nucleolar) are being expressed while at the same time, the UBE3A antinsense gene is being expressed. Especially the last one leads to no expression of the UBE3A sense gene. On the maternal chromosome the PW ICR is methylated and thus genes in that region are inhibited => UBE3A is expressed

Question 16

PW syndrome causes

Answer 16

If the PW ICR happens to be affected aka being methylated on the paternal chromosome => no snoRNAs which have crucial role in neural development. Reasons for this can be direct mutations -> Deletion of the PWS-ICR: no promoter, no transcription!
-> Deletion of the snoRNAs
-> Maternal UPD
-> Aberrant methylation of PWS-ICR

Question 17

Why parthenogenesis is a successful strategy in reptiles and other organisms but not in mice?

Answer 17

In eutherian mammals the presence of imprinted genes means sexual reproduction is necessary to ensure that both paternal and maternal chromosomes are present in the genome. In reptiles imprinting is not a thing and thus if simply the same maternal chromosomes are used it is fine