8 - epigenetics and disease Flashcards
can a genes without a disease-causing mutation be pathogenic?
yes
if they are turned on/off at the wrong point during development
epigenetic imprints
genes that have been altered epigenetically and have evaded the reprogramming of the epigenome
uniparental disomy (UPD)
when you inherit two copies of a chromosome from one parent
–> increased levels of gene expression from one parent
disorders caused by UPD
Angelman syndrome (AS) and Prader-Willi syndrome (PWS)
clinical worries due to UPD
disruption of parent-specific genomic imprinting, resulting in imprinting disorders
large blocks of homozygosity, which may lead to the uncovering of recessive genes
IGF2 in genomic imprinting
only the allele for IGF2 from the father is expressed
can cause babies to be abnormally large
how does stress alter epigenetics
DNA methylation of glucocorticoid receptor gene
prader willi syndrome (PWS)
imprinting disorder
characterised by obesity, short stature, small hands/feet, mental deficiency
maternal disomy 15 (paternal deletion of chromosome 15)
diagnosed by methylation testing
angelman syndrome
imprinting disorder
characterised by developmental deficiencies, seizures and mental retardation
loss of maternally inherited gene in chromosome 15
diagnosed by blood test to test function of UBE3A gene
importance of UBE3A gene
encodes a protein called E3 ubiquitin ligase, which is involved in targeting proteins for degradation, and it is only imprinted in the brain.
loss of UBE3A may result in abnormalities in normal protein degradation during brain development, thereby causing Angelman syndrome
result of genome hypomethylation
genome instability and inappropriate activation of oncogenes and transposable elements.
histone N-terminal tails
crucial in helping to maintain chromatin
stability and are subject to numerous modifications
Xist
X-inactive specific transcript
gene on the X chromosome
important for X chromosome inactivation
RNAi pathway
RNA interference pathway
process by which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules
X chromosomes lacking Xist
will not be inactivated
why are miRNA important
affect the expression of genes linked to the cell cycle
miRNA expression is altered in cancer cells
role of DNA methylation in disease
- long term silencing of genes.
- silencing of repetitive elements ( eg:
transposons). - X-chromosome inactivation.
- establishment and maintenance of imprinted genes.
- suppression of viral gene expression and other
deleterious elements - carcinogenesis.
Histone acetyl transferases (HATs)
class of enzymes that acetylate lysine residues in core histones --> leads to a less compact and more transcriptionally active chromatin
Histone deacetylases (HDACs)
class of enzymes that remove acetyl groups from
acetyl-lysine residues on histones
–> allows histone to wrap around the DNA
more tightly and reduces gene expression
HDAC inhibition combination therapy
phase 2 study: vorinostat combined with idarubicin and cytarabine
addition of an HDAC inhibitor to standard chemotherapy may lead to improved response rates in patients with newly diagnosed AML and MDS.
DNA methyltransferase inhibitors
inhibit the methylation of DNA and therefore has effects on gene expression.
Examples: Azacitidine and Decitabine
result of offsrping from prenatally undernourished fathers (but not mothers)
babies were heavier and more obese than offspring of fathers who had not been undernourished prenatally
effect of dutch hunger winter
severe undernourishment affected pregnant women, their unborn offspring and the offspring’s foetal germ cells.
effect of polyphenols in diet
reverse some of the epigenetic alterations
associated with malignant transformation
inhibitory effects on DNA methyltransferases
effect of high alcohol consumption on epigenetics and disease
Ethanol induces gene activation through an increase in histone H3 and H4 acetylation which may lead to immune system disfunction
