Epigenetics

Question 1

What is FGR and how frequent is it?

Answer 1

Occurs in around 5% of all pregnancies
FGR is Fetal Growth Restriction when a babys growth slows or stops in utero.

Question 2

what are the three causes of FGR?

Answer 2

chromosomal defects
placental insufficiency
enviroment

Question 3

what enviromental factors can lead to FGR?

Answer 3

• multiple gestation (twins, triplets)
• smoking
• alcohol or abusing drugs
• maternal illness or infections
• nutrition
• stress

Question 4

what can FGR lead to?

Answer 4

• babies can be stillborn
• at risk of developing lifelong disabilities (cerebral palsy)
• risk of developing non-communicable diseases in adult hood

Question 5

What do smaller babies have a higher risk of non-communicable disease wise?

Answer 5

• hypertension
• raised serum cholesterol
  -impaired glucose tolerance
• type 2 diabetes
• obesity

Question 6

name a study conducted to see baby weight compared to a disease?

Answer 6

• mortality from coronary heart disease before 65 years in 15,726 men and women in hertfordshire compared to baby weight
• correlation between smaller babies and cornonary heart disease in later life
• due to weaker hearts as smaller

Question 7

what is the Dutch Hunger Winter?

Answer 7

In 1944/45 food supplies were cut off to a city in Holland. So had around 500 calories a day. Pregnant women were exposed to the famine and therefore led to smaller babies and the offspring developed cardiovascular disease and diabetes.
- altered enzymes in blood

Question 8

What is a gene?

Answer 8

a nucleotide sequence required to direct protein synthesis

Question 9

whats the pathway of an oocyte to a blastocyst?

Answer 9

oocyte
zygote
2-cell
4-cell
8-cell
morula
blastocyst (epiblast)

Question 10

what two things will a blastocyst differentiate into?

Answer 10

fetus propa or placenta

Question 11

what are the 5 steps of formation of a blastocyst?

Answer 11

1) maturation
2) fertilisation
3) cleavage
4) compaction
5) caviation

Question 12

what initiates de novo transcription?

Answer 12

during early cleavage, the embryonic genome is gradually switched on to initiate de novo

Question 13

what regulate early on embryo development?

Answer 13

mRNA’s maternally inherited from the oocyte

Question 14

what are epigenetics

Answer 14

the study of heritable changes in gene activity that occur without a change in the DNA sequence

Question 15

what determines how tightly packed the DNA is within the chromosomes?

Answer 15

Histones

Question 16

what are epigenetic modifiers?

Answer 16

enzymes that catalyse the addition or removal of epigenetic tags

Question 17

what is the epigenome?

Answer 17

the genome-wide epigentic state
all of the epigenetic modifications within the cells genome

Question 18

how many pregnancies does FGR occur in

Answer 18

5%

Question 19

what are epigenetic tags?

Answer 19

DNA methylation
changes to the protein structure of the histones

Question 20

what are the three most studied epigenetic mechanisms?

Answer 20

1) chemical modifications of DNA (methylation)
2) Post translation modifications of histone tails
3) histone variants

Question 21

what base does DNA methylation normally occur?

Answer 21

cytosine but only if next to the base guanine (CpG)

Question 22

what catalyses the methylation of cytosine?

Answer 22

DNA methyltransferase (Dnmt)

Question 23

what types of DNA methyltransferases are there and what are they for?

Answer 23

De-novo methylation is by Dnmt3a and Dnmt3b to set up the DNA pattern
Maintenance methylation (maintains cell division after markers attached to DNA) Dnmt1

Question 24

what is the Tet enzyme?

Answer 24

undergoes oxidation reaction to convert 5-mc into 5-hmc (adds hydroxy to methylated cytosine)
can also with DNA repair ezymes convert 5-hmc to cytosine

Question 25

what can demthylated cytosine also be turned into ?

Answer 25

thymine

Question 26

what do CpGs allow for ?

Answer 26

when methylated they allow for silencing of large regions of the genome

Question 27

what are CpG islands?

Answer 27

clustered of CpGs normally in promoter or enhancer around 7% are clustered

Question 28

what sort of cytosines are found in GRE?

Answer 28

non-methylated so rna poilymerase can make direct contact with the promoter

Question 29

what are imprinted genes?

Answer 29

genes which are methylated throughout development and they need to be methylated to control their function

Question 30

what is x inactivation?

Answer 30

due to methylation when we've got two X chromosomes in the female, methylation switches off the X chromosome we're not using

Question 31

what part does methylation play in cancer?

Answer 31

methylation of the gene promoter on the site of protective genes that may protect against cell replication in cancer (can have faulty methylation)

Question 32

in terms of gene expression what is DNA methylation at CpG islands important for?

Answer 32

- Cell-specific differences in transcription - Developmental differences in transcription - Genomic imprinting

Question 33

what two processes occur where DNA methylation is critical?

Answer 33

- variable in different tissues and involved in regulating tissue-specificc gene expression patterns - permanently 'imprinted' therefore maintained and memorised in (nearly) all tissues

Question 34

what is disturbed methylation patterns?

Answer 34

involved in many human diseases (cancer, growth defects and behavioural disorders)

Question 35

what is erased in primordial germ cells?

Answer 35

methylation marks

Question 36

what happens in terms of methylation when fertilisation occurs?

Answer 36

demethylation of the entire genome occurs methylation marks are removed in a pattern as the cell can distinguish between paternal and maternal which causes this process to happne in different rates

Question 37

when does remethylation occur?

Answer 37

at the blastocyst stage in a cell-type specific manner (ICM vs TE) (Inner Cell Mass vs trifecta )

Question 38

what happens during global methylation?

Answer 38

during a preimplantation embryo - somatic and placental methylation is established - imprinted genes withstand this fluctuation

Question 39

what can effect inutero DNA methylation

Answer 39

- intrinsic factors - enviromental factors

Question 40

In imprinting what is the difference between paternal and maternal in genes?

Answer 40

- genes that promote fetal and placental growth are maternally imprinted - genes that inhibit fetal and placental growth are paternally imprinted

Question 41

what is maternal imprinting due to ?

Answer 41

it limits the use of maternal resources (making sure uterus and nutrients favour the mother - paternal is opposite)

Question 42

define imprinting

Answer 42

is a process that leads to heritable silencing of a gene on one of the parental chromosomes

Question 43

what is IGF2 and why is it important?

Answer 43

Insulin-like growth factor 2 gene - matches placental nutrient supply to fetal demand - altered IGF2 is related to FGR

Question 44

Describe the process of IGF2 maternal

Answer 44

insulator binds maternal unmethylated ICR1, H19 gene is expressed and this blocks IGF2 expression

Question 45

decribe the process of IGF2 paternal

Answer 45

paternal methylation at ICR1 prevents CTCF binding and therefore IGF2 is expressed

Question 46

what is the importance of IGF2?

Answer 46

it is a major fetal growth factor involved in differentiation, organogenesis and metabolic regulation

Question 47

what happens if IGF2 is not methylated in the paternal copy? due to loss of imprinting at the IGF2/ICR1/H19 domain

Answer 47

causes silver-russell syndrome and therefore prenatal growth failure

Question 48

what is higher umbilical cord RXRA gene promoter methylation associated with according to Godfrey, et al.Diabetes 2011?

Answer 48

- associated with low maternal early pregnancy carbohydrate intake and with greater childhood adiposity age 9 years