Epigenetics and disease Flashcards
what is fetal growth restriction (FGR)?
Fetal growth restriction (FGR) is most often defined as an estimated fetal weight less than the 10th percentile for gestational age by prenatal ultrasound evaluation. The condition is associated with a number of short-term and long-term complications that can severely impact the quality of life.
A baby’s growth slows or stops in utero - the embryo and the fetus do not grow to their full potential, effecting birth and lifecourse
can be caused by altered placental gene expression
give three things that can cause fetal growth restriction
- Chromosomal defects
- Placental insufficiency
- Environment ~ multiple gestation (twins, triplets), smoking, alcohol, or abusing drugs, maternal illness or infections, nutrition or stress
fetal growth restriction leads to what potential consequences
- Babies can be stillborn
- At risk of developing lifelong disabilities (e.g. cerebral palsy)
- At risk of developing non-communicable diseases in adulthood
how do we know a pregnancy has fetal growth restriction?
we can monitor the fetus through ultrasound and compare to growth charts
why is a healthy placenta/baby the foundation of life long health?
because it underlies the furture development of the baby, from epigenetic mark to laying down/detting up cell numbers and tissue structures
what things in the meternal environment can effect the placenta and so the fetal development?
body composition
diet/nutrients
toxins/drugs
what factors contributes to a healthy placenta?
(4)
Size and structure
Transport capacity – nutrients, toxins, igG
Blood flow – maternal and fetal
Metabolism – nutrients, drugs
what is the functional unit of the placenta?
placental cotyledon
fetal vessels are bathed with maternal blood in the placenta surrounded by epithelial cell layer
how are amino acids transported from mother to fetus
Amino acids are transported from mother to fetus though exchangers – controlled by gene expression within the simple cell layer of the placenta
Syncytiotrophoblasts of the placenta contain exchanges, transporting amino acids from one side where the mohters blood is to the other where fetal blood is
what happens to the fetus if they dont receive the proteins?
what can this lack in supply be caused by
It can impact upon development of organs and set it up for diseases later in life
caused by changes in gene expression
describe the evidence that shows smaller babies have a higher risk of non communicable diseases
Dr Barker in Southampton looked at people with a range of illnesses then went back to look at their birth weight - they saw a correlation with low birth weight and different conditions
Low birth weight saw a change in: hypertension, raised serun cholesterol, impaired glucose tolerance, type 2 diabetes, obesity
potentially due to fewer cells being layed down in various organs making them weaker and more suseptible with greater risk of failing
what was the dutch hunger winter and how did it help us discover the consequences of lack of nutrients?
In 1944/45 a town was cut off by bombing of the railways being they could not
People consumed an average of only 500kcal a day
The women expoed to famin during pregnancy had smaller babies
These babies developed cardiovascular disease, disbetes etc.
Lack of nutrients altered their gene expression that affected their pathological status later in their lifecourse
what things in the maternal body can have physiological impacts by changing gene expression?
(4)
environment, nutrition, changes to hormones and stress levels
at what stage does the zygote begin to differentiate
at the blastocyst stage
what regulates the embryo early on
mRNAs inherited from the oocyte
maternally inherited
when is the embryonic genome gradually turned on?
during early cleavage
describe how body composition can affect the fetus
it was shown that mothers with a higher pre-pregnant arm muscle mass had a higher TAT mRNA level (increased neonatal lean mass)
Stem cells from donated umbilical cords are examined and the cells from babies who had mothers of normal weight during their first prenatal visit and mothers who were obese at the time.
They then grew the cells into fat and muscle cells in a lab. Boyle noted that none of the women gained excessive weight during their pregnancies.
The researchers noticed a 30 percent higher fat content in both types of cells in the children whose mothers were obese.
what is epigenetics?
The study of heritable changes in gene regulation activity that occur without a change in the DNA sequence
what are epigenetic mechanisms?
give four examples
the factors that determine which genes are switched on and off at certain times
DNA methylation, histone modification, histone variants and non coding RNAs
how much of the genome is made out of coding sequences?
5%
what things determine whether a gene is transcribed
RNA pols ability to attach to control element/DNA
determined by the packaging of the nucleosomes
packaging caused by the modification s on the histone proteins
what is the epigenome?
the genome wide epigenetics - all of the epigenetic modification in the cells genome
what are epigenetics tags and what are epigenetic modifiers?
Epigenetic tags: Epigenetic marks or modifications
Epigenetic modifiers: Enzymes that catalyse the addition or removal of epigenetic tags
what is the most commonly methylated base?
Cytosine next to guanine
Cytosine (CpG) is methylated to 5-methyl cytosine (5mC)
how does DNA methylation affect transcription?
Provides a physical block for transcription factors binding, can also attract methyl binding proteins to block or change the DNA transcription
what is a CpG dinucleotide?
Palindromic Motif – C then G from 5’ to 3’ on both strands
what enzymes catalyse DNA methylation?
DNA methyltransferase
what is the function of Dnmt3a & Dnmt3b?
de novo methylation of the DNA
what is the function of Dnmt1?
maintenance of DNA methylation
- adds on the methylation to the sister strand based on the mark on the template strand
what enzyme removes the methylation marks on DNA?
how?
Tet enzymes convert 5-methyl cytosine (5mC) to 5-hydroxymethylcytosine (5-hmc)
Deaminated to thymine
Both repaired as part of the normal DNA mechanism
what reasons could there be for a methylated CpG island on a control element
imprinted genes
x-inactivation
cancer
environmental influences
give a common example of how dna methylation at CpG islands represses gene expression
Hypermethylation of 1 X chromosome in females
As females have 2 X chromosomes (males only 1) – random switch-off
switching off of one of the x-chromosomes can lead to mosaic patterns in the cells
X inactivation represses of gene expression is involved in what three major things
– Cell-Specific Differences in Transcription
– Developmental Differences in Transcription
– Genomic imprinting
cell differentiation and tissue specific expression
in what two processes is DNA methylation critical?
- variable in different tissues and involved in
regulating tissue-specific gene expression patterns - permanently ‘imprinted‘, therefore maintained and memorised in (nearly) all tissues
in what two processes in DNA methylation critical?
- variable in different tissues and involved in
regulating tissue-specific gene expression patterns - permanently ‘imprinted‘, therefore maintained and memorised in (nearly) all tissues
disturbed methylation patterns are involved with what human diseases
cancer
growth defects
behavioural disorders
methylation marks are erased in what specific cell types
primordial germ cells
oocytes and sperm continue to re-acquire methylation marks unti/during maturation yet in different time frames and to different extents
when and how does the fertilised egg remove the methylation marks of the parental DNA
Following fertilisation
The cell can recognise which genome comes form the sperm and which from the egg
The fertilised egg removes all of the methylation marks using TET, the maternal and paternal marks occurs along different timelines, with the paternal removes faster
when does remethylation occurs in the fertilised egg?
Re-methylation begins at the blastocyst stage in a cell- type specific manner (ICM vs TE) by DNMT3a and DNMT3b
TE has a much lower methylation pattern than the ICM – the ICM has more functions to carry out so needs more genes turned on
DNMT1 maintains these marks – adds on the methylation to the sister strand based on the mark on the template strand
what genes withstand the fluctuation during global demethylation in the preimplantation embryo?
imprinted genes
what occurs during global demethylation in the preimplantation embryo
→ Somatic & placental methylation established
→ Imprinted genes withstand this fluctuation
what is responsible for normal epigenetic drift?
intrinsic and environmental factors affecting remethylation every time the cell divides
leading to altered chromatin functions and an altered phenotypes