Epigenetics and Abnormal Gene Expression Flashcards
what is x-chromosome inactivation?
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
what initiates the mechanism of silencing?
Xist - x-inactive-specific-transcript
what mechanism follows silencing?
DNA methylation
what is Rett Syndrome?
- 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
what is genomic imprinting?
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.
what are features of genomic imprinting?
- ~80 imprinted genes on autosomes
- imprinted genes only expressed from one allele
- dependent on parental origin
- imprinting resets on passage through germline
what are features of the mechanism of imprinting?
- must be somatically stable
- must be reversible during gametogenesis
- DNA methylation is the best candidate (=epigenetic modification)
what is uniparental disomy?
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
what are the results of UPD on chromosome 15?
Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS)
what are the results of UPD on chromosome 11?
Wilms’ tumour
which UPD related condition is a result of maternal deficiency?
Angelman Syndrome
which UPD related condition is a result of paternal deficiency?
Prader- Willi Syndrome
what causes uniparental disomy?
non-disjunction in meiosis II
what causes uniparental heterodisomy?
non-disjunction in meiosis I
what does non-disjunction in meiosis II cause?
uniparental disomy
what does non-disjunction in meiosis I cause?
uniparental heterodisomy
what are some diseases associated with genomic imprinting?
- beckwith-wiedman syndrome (BWS)
- fragile x syndrome
- myotonic dystrophy (congenital)
- prader-willi syndrome
- angelman syndrome
- wilms’ tumour
what drug is approved for the treatment of patients with myelodysplastic syndrome?
VIDAZA
what is VIDAZA used to treat?
myelodysplastic syndrome
what is Brg1?
- chromatin regulator that “opens” chromatin and suppresses tumours
- low BRg1-expressing tumours have worse outcome
what mechanisms are involved in epigenetic gene silencing?
- DNA methylation
- histone modifications
- nucleosome remodelling
what does DNA methylation do?
inhibits gene transcription
how does DNA methylation inhibit gene transcription?
- 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
what are the differences between heterochromatin and euchromatin?
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
