8 - epigenetics and disease

Question 1

can a genes without a disease-causing mutation be pathogenic?

Answer 1

yes

if they are turned on/off at the wrong point during development

Question 2

epigenetic imprints

Answer 2

genes that have been altered epigenetically and have evaded the reprogramming of the epigenome

Question 3

uniparental disomy (UPD)

Answer 3

when you inherit two copies of a chromosome from one parent

–> increased levels of gene expression from one parent

Question 4

disorders caused by UPD

Answer 4

Angelman syndrome (AS) and Prader-Willi syndrome (PWS)

Question 5

clinical worries due to UPD

Answer 5

disruption of parent-specific genomic imprinting, resulting in imprinting disorders

large blocks of homozygosity, which may lead to the uncovering of recessive genes

Question 6

IGF2 in genomic imprinting

Answer 6

only the allele for IGF2 from the father is expressed

can cause babies to be abnormally large

Question 7

how does stress alter epigenetics

Answer 7

DNA methylation of glucocorticoid receptor gene

Question 8

prader willi syndrome (PWS)

Answer 8

imprinting disorder
characterised by obesity, short stature, small hands/feet, mental deficiency

maternal disomy 15 (paternal deletion of chromosome 15)
diagnosed by methylation testing

Question 9

angelman syndrome

Answer 9

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

Question 10

importance of UBE3A gene

Answer 10

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

Question 11

result of genome hypomethylation

Answer 11

genome instability and inappropriate activation of oncogenes and transposable elements.

Question 12

histone N-terminal tails

Answer 12

crucial in helping to maintain chromatin

stability and are subject to numerous modifications

Question 13

Xist

Answer 13

X-inactive specific transcript

gene on the X chromosome
important for X chromosome inactivation

Question 14

RNAi pathway

Answer 14

RNA interference pathway

process by which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules

Question 15

X chromosomes lacking Xist

Answer 15

will not be inactivated

Question 16

why are miRNA important

Answer 16

affect the expression of genes linked to the cell cycle

miRNA expression is altered in cancer cells

Question 17

role of DNA methylation in disease

Answer 17

• 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.

Question 18

Histone acetyl transferases (HATs)

Answer 18

class of enzymes that acetylate lysine residues in
core histones --> leads to a less compact and more transcriptionally active chromatin

Question 19

Histone deacetylases (HDACs)

Answer 19

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

Question 20

HDAC inhibition combination therapy

Answer 20

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.

Question 21

DNA methyltransferase inhibitors

Answer 21

inhibit the methylation of DNA and therefore has effects on gene expression.

Examples: Azacitidine and Decitabine

Question 22

result of offsrping from prenatally undernourished fathers (but not mothers)

Answer 22

babies were heavier and more obese than offspring of fathers who had not been undernourished prenatally

Question 23

effect of dutch hunger winter

Answer 23

severe undernourishment affected pregnant women, their unborn offspring and the offspring’s foetal germ cells.

Question 24

effect of polyphenols in diet

Answer 24

reverse some of the epigenetic alterations
associated with malignant transformation

inhibitory effects on DNA methyltransferases

Question 25

effect of high alcohol consumption on epigenetics and disease

Answer 25

Ethanol induces gene activation through an increase in histone H3 and H4 acetylation which may lead to immune system disfunction