epigenetics and abnormal gene expression

Question 1

what is gene silencing?

Answer 1

the regulation of gene expression in a cell to prevent the expression of a certain gene which is done by:
- DNA methylation
- nucleosome remodeling
- histone modifications

Question 2

what does DNA methylation do?

how does DNA methylation carry out this process?

Answer 2

• DNA methylation inhibits gene transcription (DNA to RNA is transcription)
• Methylation prevents the binding of transcription factors to the promoter and inhibits transcription by converting chromatin from an open to a closed conformation:

1. Methyl CpG binding proteins (promotor regions) contain a methyl binding domain that specifically recognizes methylated CpGs
2. Recruits other proteins such as histone deacetylases which remove acetyl groups, favouring compact chromatin

Question 3

give an example of X-linked syndrome with variable phenotype,
give an example of a paternal deficiency
give an example of a maternal deficiency

Answer 3

1. Rett Syndrome
2. Prader-Willi Syndrome
3. Angelman Syndrome

Question 4

describe Rett Syndrome

Answer 4

1. it is a dominant X-linked neurodegenerative disorder
2. it affects 1:10,000-15,000 (females only)
3. it is caused by a mutation in the gene encoding in Methyl-CpG-binding protein 2 (MeCP2), which in turn leads to loss of gene silencing at many loci.
4. due to defects in imprinted genes: defective expression in brain tissue

Question 5

describe Prader-Willi syndrome

Answer 5

1. causes mental retardation and obesity due to metabolism defects
2. rare genetic condition that causes a wide range of physical
   symptoms, learning difficulties and behavioural problems
3. caused by a fault in a group of genes on chr15
4. Most cases of Prader-Willi syndrome (about 70%) occur when a segment of the paternal chromosome 15 is deleted genes which means there’s no active copy of chr 15 in the child’s brain. In another 25%, a person has two copies of chr 15 inherited from the mother. This is known as (maternal) uniparental disomy

Question 6

describe Angelman syndrome

Answer 6

1. mental retardation aka. happy puppet syndrome
2. jerky movements + inappropriate laughter
3. genetic disorder that affects the nervous system and causes
   severe physical and intellectual disability
4. caused when the Angelman gene, known as UBE3A, is either absent or malfunctions
5. In most cases of Angelman syndrome (about 70%),
   the child’s maternal copy of the UBE3A gene is missing (deleted),
   which means there’s no active copy of the UBE3A gene in the
   child’s brain. In a small number of cases, Angelman syndrome
   occurs when a child inherits two copies of chromosome 15
   from the father, rather than inheriting one from each parent.
   This is known as (paternal) uniparental disomy

Question 7

DNA higher order structure influences gene expression

what are the differences between heterochromatin and euchromatin?

Answer 7

Heterochromatin
- highly condensed in interphase
- transcriptionally inactive ( containing a few genes )
- replicates late in S phase

Euchromatin
- organised in 30nm fiber during interphase
- transcriptionally active
- replicates early in S phase

^spreading of heterochromatin in euchromatin regions causes cell to cell variability in gene expression = position effect - stops gene transcription

Question 8

describe chromosome inactivation (big example of gene silencing)

Answer 8

there is one two many x chromosomes in females (men have XY chromosomes and women have XX) and so females need to silence one X-chromosome - aka. X chromosome inactivation.

this silencing is initiated by X-ist (X-inactive-specific-transcript)
X-inactive-transcript ‘marks’ the inactive X chromosomes as it is only expressed from inactive X-chromosome and codes for an RNA. there is no protein product and RNA remains in the nucleus.
This is followed by DNA methylation.

Question 9

describe Klinefelter’s syndrome

Answer 9

• 1 X chromosome should remain active:
  
  • so in rare examples such as a male with Klinefelter’s
    syndrome (where the genotype is 47XXY). and the number of
    Barr bodies (inactive X chromosome) would be 1

Question 10

what is genomic imprinting

Answer 10

Genomic imprinting is the process by which only one copy of a gene in an individual (either from their mother or their father) is expressed, while the other copy is suppressed.

Question 11

what is uniparental disomy?

Answer 11

• Both copies of a chromosome are inherited from the same parent (when both imprinted genes are from the same parent)
• The individual is missing the chromosome from one of the parents

(when genomic imprinting goes wrong)