Epigenetics Flashcards
What is FGR and how frequent is it?
Occurs in around 5% of all pregnancies
FGR is Fetal Growth Restriction when a babys growth slows or stops in utero.
what are the three causes of FGR?
chromosomal defects
placental insufficiency
enviroment
what enviromental factors can lead to FGR?
- multiple gestation (twins, triplets)
- smoking
- alcohol or abusing drugs
- maternal illness or infections
- nutrition
- stress
what can FGR lead to?
- babies can be stillborn
- at risk of developing lifelong disabilities (cerebral palsy)
- risk of developing non-communicable diseases in adult hood
What do smaller babies have a higher risk of non-communicable disease wise?
- hypertension
- raised serum cholesterol
-impaired glucose tolerance - type 2 diabetes
- obesity
name a study conducted to see baby weight compared to a disease?
- 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
what is the Dutch Hunger Winter?
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
What is a gene?
a nucleotide sequence required to direct protein synthesis
whats the pathway of an oocyte to a blastocyst?
oocyte
zygote
2-cell
4-cell
8-cell
morula
blastocyst (epiblast)
what two things will a blastocyst differentiate into?
fetus propa or placenta
what are the 5 steps of formation of a blastocyst?
1) maturation
2) fertilisation
3) cleavage
4) compaction
5) caviation
what initiates de novo transcription?
during early cleavage, the embryonic genome is gradually switched on to initiate de novo
what regulate early on embryo development?
mRNA’s maternally inherited from the oocyte
what are epigenetics
the study of heritable changes in gene activity that occur without a change in the DNA sequence
what determines how tightly packed the DNA is within the chromosomes?
Histones
what are epigenetic modifiers?
enzymes that catalyse the addition or removal of epigenetic tags
what is the epigenome?
the genome-wide epigentic state
all of the epigenetic modifications within the cells genome
how many pregnancies does FGR occur in
5%
what are epigenetic tags?
DNA methylation
changes to the protein structure of the histones
what are the three most studied epigenetic mechanisms?
1) chemical modifications of DNA (methylation)
2) Post translation modifications of histone tails
3) histone variants
what base does DNA methylation normally occur?
cytosine but only if next to the base guanine (CpG)
what catalyses the methylation of cytosine?
DNA methyltransferase (Dnmt)
what types of DNA methyltransferases are there and what are they for?
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
what is the Tet enzyme?
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
what can demthylated cytosine also be turned into ?
thymine
what do CpGs allow for ?
when methylated they allow for silencing of large regions of the genome
what are CpG islands?
clustered of CpGs normally in promoter or enhancer around 7% are clustered
what sort of cytosines are found in GRE?
non-methylated so rna poilymerase can make direct contact with the promoter
what are imprinted genes?
genes which are methylated throughout development and they need to be methylated to control their function
what is x inactivation?
due to methylation when we’ve got two X chromosomes in the female, methylation switches off the X chromosome we’re not using
what part does methylation play in cancer?
methylation of the gene promoter on the site of protective genes that may protect against cell replication in cancer (can have faulty methylation)
in terms of gene expression what is DNA methylation at CpG islands important for?
- Cell-specific differences in transcription
- Developmental differences in transcription
- Genomic imprinting
what two processes occur where DNA methylation is critical?
- variable in different tissues and involved in regulating tissue-specificc gene expression patterns
- permanently ‘imprinted’ therefore maintained and memorised in (nearly) all tissues
what is disturbed methylation patterns?
involved in many human diseases (cancer, growth defects and behavioural disorders)
what is erased in primordial germ cells?
methylation marks
what happens in terms of methylation when fertilisation occurs?
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
when does remethylation occur?
at the blastocyst stage in a cell-type specific manner (ICM vs TE) (Inner Cell Mass vs trifecta )
what happens during global methylation?
during a preimplantation embryo
- somatic and placental methylation is established
- imprinted genes withstand this fluctuation
what can effect inutero DNA methylation
- intrinsic factors
- enviromental factors
In imprinting what is the difference between paternal and maternal in genes?
- genes that promote fetal and placental growth are maternally imprinted
- genes that inhibit fetal and placental growth are paternally imprinted
what is maternal imprinting due to ?
it limits the use of maternal resources (making sure uterus and nutrients favour the mother - paternal is opposite)
define imprinting
is a process that leads to heritable silencing of a gene on one of the parental chromosomes
what is IGF2 and why is it important?
Insulin-like growth factor 2 gene
- matches placental nutrient supply to fetal demand
- altered IGF2 is related to FGR
Describe the process of IGF2 maternal
insulator binds maternal unmethylated ICR1, H19 gene is expressed and this blocks IGF2 expression
decribe the process of IGF2 paternal
paternal methylation at ICR1 prevents CTCF binding and therefore IGF2 is expressed
what is the importance of IGF2?
it is a major fetal growth factor involved in differentiation, organogenesis and metabolic regulation
what happens if IGF2 is not methylated in the paternal copy? due to loss of imprinting at the IGF2/ICR1/H19 domain
causes silver-russell syndrome and therefore prenatal growth failure
what is higher umbilical cord RXRA gene promoter methylation associated with according to Godfrey, et al.Diabetes 2011?
- associated with low maternal early pregnancy carbohydrate intake and with greater childhood adiposity age 9 years
