Epigenetics and Abnormal Gene Expression

Question 1

what is x-chromosome inactivation?

Answer 1

X-inactivation (also called lyonization) is a process by which one of the copies of the X chromosome present in females is inactivated.

The inactive X chromosome is silenced by its being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin

Question 2

what initiates the mechanism of silencing?

Answer 2

Xist - x-inactive-specific-transcript

Question 3

what mechanism follows silencing?

Answer 3

DNA methylation

Question 4

what is Rett Syndrome?

Answer 4

• dominant x-linked syndrome
• variable phenotypes
• neurodegenerative disorder
• affects females only
• caused by mutation in gene encoding MeCP2 which leads to loss of gene silencing at many loci

Question 5

what is genomic imprinting?

Answer 5

the epigenetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. If the allele inherited from the father is imprinted, it is thereby silenced, and only the allele from the mother is expressed.

Question 6

what are features of genomic imprinting?

Answer 6

• ~80 imprinted genes on autosomes
• imprinted genes only expressed from one allele
• dependent on parental origin
• imprinting resets on passage through germline

Question 7

what are features of the mechanism of imprinting?

Answer 7

• must be somatically stable
• must be reversible during gametogenesis
• DNA methylation is the best candidate (=epigenetic modification)

Question 8

what is uniparental disomy?

Answer 8

can result in a disruption of the expression of imprinted genes:

• both copies of a chromosome are inherited from the same parent
• individual is missing the chromosome from one parent
• expression altered of imprinted genes on affected chromosome

Question 9

what are the results of UPD on chromosome 15?

Answer 9

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

Question 10

what are the results of UPD on chromosome 11?

Answer 10

Wilms’ tumour

Question 11

which UPD related condition is a result of maternal deficiency?

Answer 11

Angelman Syndrome

Question 12

which UPD related condition is a result of paternal deficiency?

Answer 12

Prader- Willi Syndrome

Question 13

what causes uniparental disomy?

Answer 13

non-disjunction in meiosis II

Question 14

what causes uniparental heterodisomy?

Answer 14

non-disjunction in meiosis I

Question 15

what does non-disjunction in meiosis II cause?

Answer 15

uniparental disomy

Question 16

what does non-disjunction in meiosis I cause?

Answer 16

uniparental heterodisomy

Question 17

what are some diseases associated with genomic imprinting?

Answer 17

• beckwith-wiedman syndrome (BWS)
• fragile x syndrome
• myotonic dystrophy (congenital)
• prader-willi syndrome
• angelman syndrome
• wilms’ tumour

Question 18

what drug is approved for the treatment of patients with myelodysplastic syndrome?

Answer 18

VIDAZA

Question 19

what is VIDAZA used to treat?

Answer 19

myelodysplastic syndrome

Question 20

what is Brg1?

Answer 20

• chromatin regulator that “opens” chromatin and suppresses tumours
• low BRg1-expressing tumours have worse outcome

Question 21

what mechanisms are involved in epigenetic gene silencing?

Answer 21

• DNA methylation
• histone modifications
• nucleosome remodelling

Question 22

what does DNA methylation do?

Answer 22

inhibits gene transcription

Question 23

how does DNA methylation inhibit gene transcription?

Answer 23

• prevents binding of transcription factors to the promoter and inhibits transcription by converting chromatin from an open to closed formation
• methyl CpG binding proteins contain a methyl binding domainthat specifically recognizes methylated CpGs
• recruits other proteins such as histone deacetylases whichremove acetyl groups, favouring compact chromatin

Question 24

what are the differences between heterochromatin and euchromatin?

Answer 24

H: highly condensed in interphase
E: organised in 30nm fibre during interphase

H: transcriptionally inactive (contains few genes)
E: transcriptionally active

H: replicates late in S phase
E: replicated early in S phase

Question 25

what is the result of the spreading of heterochromatin into euchromatic regions?

Answer 25

cell to cell variability in gene expression

Question 26

what is position effect?

Answer 26

the spreading of heterochromatin into euchromatic regions causing cell to cell variability in gene expression

Question 27

what are desirable features for an imprinting mechanism?

Answer 27

- must be somatically stable - must be reversible during gametogenesis (DNA methylation is the best candidate = epigenetic modification)

Question 28

what are features of androgenetic cells/embryos?

Answer 28

- poor growth of embryo - large placenta - non-viable

Question 29

what are features of gynogenetic cells/embryos?

Answer 29

- embryo OK - small placenta - non-viable

Question 30

which chromosome are both PWS and AS both linked to the same imprinted region of?

Answer 30

chromosome 15

Question 31

what occurs with DNA methylation in cancer?

Answer 31

tumour suppressor genes are silenced