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imed2004 > Epigenetics 2 > Flashcards

Epigenetics 2 Flashcards

1
Q

Why is DNA methylation the best understood mechanism of epigenetic gene regulation?

A

It occurs in bacteria at restriction enzyme sites and in vertebrates.

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2
Q

How much DNA is methylated in mammals?

A

5-methyl C residues within CpG dinucleotides are common (70 - 80% methylated CG in mammals)

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3
Q

What are the patterns of DNA methylation?

A

CpG, CpNpG and CpHpH (H- A, T or C)

Methylation of C is common in plants and rare in animals

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4
Q

What part of DNA is often methylated?

A

Most genes have GC rich areas of DNA in their promoter regions referred to as CpG islands

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5
Q

What are CpG islands?

A

Areas that have many GpC repeats

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6
Q

What does methylation of C residues within CpG islands do?

A

Leads to gene silencing/repression

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7
Q

Where do methyl groups project?

A

Into the major groove of DNA

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8
Q

What enzymes add methyl group to DNA? What are they important for?

A

DNA methyltransferases:

3 DNMTs required for establishment and maintenance of methylation patterns: DNMT1, 3a, and 3b

2 DNMTs may have more specialized but related functions: DNMT2 and DNMT3L

DNA methylation is essential for the normal control of gene expression in development

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9
Q

How does Cytosine become thymine?

A

5-methylcytosine can spontaneously be deaminated to form Thymine

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10
Q

What is the role of DNA methylation in cells?

A

It is essential for the normal control of gene expression in development. (~1.5% of human DNA is 5-methylcytosine)

in somatic cells 5-methylcytosine is almost exclusively in CpG sites but this is not the case in embryonic stem cells.

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11
Q

What happens to DNA methylation during development?

A

methylation marks are erased prior to the blastocyst stage and then methylation restarts again in the embryo.

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12
Q

What does DNMT1 do?

A

Appears responsible for maintenance of established patterns of DNA methylation by following replication fork and adding methylation marks to newly synthesized DNA

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13
Q

What do DNMT3a and 3b do?

A

Seem to mediate establishment of new or de novo DNA methylation patterns.

DNMT3b may assist DNMT1 in maintaining normal gene hypermethylation (in diseased cells such as cancer cells).

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14
Q

What is the difference between maintenance methylation and de novo methylation?

A

De novo methylation: Unmethylated DNA is becoming methylated on its own.

Maintenance methylation allows replicated DNA to be methylated again maintaining original methylation pattern (methylation patterns have a “memory”)

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15
Q

What does methylation do to chromatin?

A

It condenses chromatin (transcription repressed)

Demethylation has the opposite effect

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16
Q

What are the consequences of low level of methylation in DNA besides expression?

A

Chromosome instability at that site. (Highly active DNA is more likely to be duplicated, deleted, and moved)

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17
Q

What is the consequence of high level of methylation besides less active transcription?

A

Genes that keep cell growth in check, genes that repair damaged DNA, and genes that initiate programmed cell death are all switched off.

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18
Q

How is DNA methylation related to Histone acetylation?

A

More unmethylated DNA = acetylation of histones

Less DNA methylation = Histone hypoacetylation

19
Q

What are euchromatin and heterochromatin?

A

Euchromatin: regions with high translocational activity

Heterochromatin are regions with low or no transcriptional activity.

20
Q

How does demethylation take place?

A

Ten-eleven translocation (TET) family of 5mC hydroxylases include TET1, 2, and 3

21
Q

How do TET family proteins carry out their action?

A

Promote DNA demethylation by binding to CpG rich regions to prevent unwanted DNA methyltransferase activity and by converting via hydroxylase activity.

22
Q

What intermediates are produced from 5mC by TET enzymes?

A

5mC -> 5hydroxymC -> 5-formylcytosine -> 5-carboxylcytosine

23
Q

What do TET proteins do overall?

A

They regulate transcriptional activation and repression (TET1)

Tumour suppression (TET2)

DNA methylation reprogramming processes (TET3)

24
Q

What are epigenetic mutations?

A

Inherited defects that have an effect through epigenetic mechanisms

25
Q

What are the implications of epigenetic factors to cancer?

A

Epigenetic mechanisms are responsible for silencing tumour suppressor genes

Activation of oncogenes may be useful in diagnosis and monitoring

Therapeutic agents

26
Q

What are imprinting disorders?

A

Disorders that can result from abnormal methylation of key genes in growth and development

27
Q

What are X-inactivation patterns?

A

Can explain disease expression in X-linked disorders

28
Q

What does information about epigenetic tell us about developmental origins of health and disease?

A

Diet and environment during foetal development, infancy, and childhood can affect adulthood through epigenetic mechanisms

29
Q

What is fragile X syndrome?

A

X-linked dominant disease that results in intellectual disability, behavioural and learning challenges

30
Q

What is fragile X syndrome the most common cause of?

A

Autism spectrum disorder (5% of patients with fragile X)

31
Q

What is the most common cause of fragile X disorder?

A

Expansion of a CGG triplet repeat region in the 5’UTR of the FMR1 gene (Familial Mental Retardation 1)

This is because having more than 200 repeats of CGG results in silencing of the gene (C methylation and transcription silencing)

32
Q

What happens to repeat length in fragile X syndrome with each generation?

A

It increases in length with each generation (hence why premutation can have no visible symptoms)

33
Q

What is Rett syndrome?

A

Neurological disorder of the brain’s grey matter resulting in decelerated head growth rate.

34
Q

What are the symptoms of Rett’s syndrome?

A

Small head, hands and feet

~80% have seizures and no verbal skills

~50% do not walk

35
Q

Why is Rett’s syndrome only seen in females?

A

Males die in utero or shortly after birth

36
Q

What causes Rett’s syndrome?

A

Mutation in MECP2 gene and this is mostly a de novo mutation.

37
Q

How does DNA methylation relate to cancer?

A

Tumour suppressor genes are often silenced in cancer cells due to hypermethylation.

However genomes of cancer cells are hypomethylated overall.

For certain cancers like colon cancer, hypermethylation is detectable early and could be a biomarker of the disease

The hypermethylation often occurs at genes involved in cell cycle regulation, tumour cell invasion, and DNA repair

38
Q

What is the Tumour Suppressor gene that is increasingly methylated in Hodgkin’s lymphoma?

A

RASSF1A

39
Q

What is biallelic gene expression?

A

More prevalent form of gene expression where both alleles of a gene are transcribed

40
Q

What is monoallelic gene expression?

A

1 of the 2 genes is active while the other is silent

41
Q

How is monoallelic expression controlled?

A

It is either dependent on parental origin (genomic inprinting) or random (fragile X)

42
Q

What is most common form of gene expression? (no expression, monoallelic, or biallelic expression)

A

Biallelic

43
Q

What is genetic imprinting?

A

DNA methylation may develop differently for each sex during gamete formation, offspring inherit an active (demethylated) copy or an inactive copy (methylated) and this is called genomic imprinting

imed2004 (22 decks)

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