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Genomics > The Epigenome > Flashcards

The Epigenome Flashcards

1
Q

What is the genome?

A

The complete set of genetic material in a cell

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2
Q

How is the genome organised?

A

It exists in a cell as an organised structure made up of a number of macromolecules with DNA as the primary building block. Histones and other proteins provide a support around which the DNA is wound. These structures are then organised in 3D to form fibres and ultimately chromosomes

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3
Q

What is a nucleosome?

A

Histone proteins and DNA that forms the first level of packaging

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4
Q

How is DNA packaged?

A
  • Nucleosomes are wound to form 30nm fibres
  • Fibres are wound up further with scaffold proteins to generate higher-order structures
  • Chromosomes are the most densely packed form of genomic DNA
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5
Q

What is the epigenome?

A

The sum of all the heritable changes in the genome that do not occur in the primary DNA sequence and that effect gene expression.

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6
Q

What is an epigenetic change?

A

A change in phenotype but not in genotype

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7
Q

What are the epigenetic mechanisms?

A

DNA methylation
Histone modification
X-inactivation
Genomic imprinting

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8
Q

What is DNA methylation?

A

It is the addition of a methyl group in the 5’ position of a cytosine.

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9
Q

What catalyses DNA methylation?

A

DNA methyltransferase enzymes

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10
Q

What are the DNA methyltransferase enzymes?

A

DNMT1, DNMT3a and DNMT3b

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11
Q

What provides the methyl group in DNA methylation?

A

S-Adenosyl Methionine

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12
Q

How does DNA methylation occur in differentiated cells?

A

It occurs in CpG dinucleotides

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13
Q

How is DNA demethylated?

A

Through a series of steps:
1. 5-methylcytosine is converted via TET into 5-hydroxymethylcytosine as there is an addition of an OH onto the 5th carbon.

  1. Then TET converts this into 5-formylcytosine (an aldehyde).
  2. Then TET converts this into 5- carboxycytosine as an COOH group is added.
  3. TDG and BER occur to convert 5-carboxycytosine, 5-formylcytosine or 5-hydroxycytosine back into cytosine through passive demethylation.
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14
Q

What is TET?

A

It is Ten-Eleven Translocation enzyme

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15
Q

What is TDG?

A

Thymidine DNA glycosylase

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16
Q

What is BER?

A

Base Excision Repair

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17
Q

When does passive demethylation occur?

A

It occurs during replication

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18
Q

What is the importance of DNA Methylation?

A
  • Turns off transcription by preventing binding of the transcription factors.
  • Patterns change during development and are an important mechanism for controlling gene expression
19
Q

What is histone modification?

A
  • The addition of chemical groups to the proteins that make up the nucleosome.
20
Q

How many histone modifications are there and what is there function?

A

About 100 modifications and many are of unknown functino

21
Q

What are the common histone modifications?

A

Acetylation and Methylation

22
Q

How are histone modifications named?

A

Based on the histone, the amino acid and the actual modification. For example, H3K4Me3 means on histone 3, the lysine at position 4 and it is tri-methylated

23
Q

What are histone writers? Give examples

A

Enzymes that add histone modifications. For example - Histone Acetyltransferase - HAT1
- Histone Methyltransferase - EHMT1

24
Q

What are histone erasers? Give examples

A

Enzymes that remove histone modifications.
For example:
- Histone deactylase HDAC1
- Histone demethylase KDM1

25
Q

What are histone readers? Give examples

A

Proteins that bind to the histone modification and alter gene activity and protein production.
For example:
- Bromodomain and extra-terminal (BET) proteins - BRD2
- Chromodomain proteins - CBX1

26
Q

Function of histone acetylation at lysine

A

At lysine residues, it relaxes the chromatin structure and makes it accessible for transcription factors

27
Q

Function of histone methylation

A

More complex than acetylation. Can repress or activate transcription depending on where it occurs

28
Q

What does the concurrence of histone modifications mean?

A

They can interact or modify each other

29
Q

What is X-inactivation?

A

Inactivation of one of the two X chromosomes in every somatic cell in females

30
Q

Why is X-inactivation required?

A

This is needed as the Y chromosome has virtually no genes, so there is only one copy of each X chromosome gene in males but in females, it is needed to make sure there is the same number of active copies of every gene in each somatic cell.

31
Q

How does X-inactivation occur?

A
  • The Xist gene is transcribed as a long non-coding RNA (IncRNA) from the X-inactivation centre (Xic) and binds all over the X-chromosome.
  • Histone acetylation removed and histone and DNA methylation occurs
  • The inactive X-chromosome is heterochromatic - Barr body.
  • Tsix is derived by transcription in the opposite direction and antagonises Xist RNA to keep one X active.
32
Q

Give an example of an animal that has undergone X-inactivation

A

All tortiseshell cats are female. This is because they have one X with an active orange fur allele and one X with an active black fur allele. Random X-inactivation results in patches of orange and black fur.

33
Q

What is genomic imprinting?

A

Imprinting is the selective expression of genes related to the parental origin of the gene copy.

34
Q

How are imprinted genes found together?

A

In clusters.

35
Q

How many imprinted genes are there?

A

Very few imprinted genes - approximately 250

36
Q

What mediates gene imprinting?

A

The imprinting control regions (ICRs)

37
Q

How is one gene silenced in imprinting?

A

One copy is silenced by DNA methylation catalysed by DMNT3a and histone methylation leading to inactivation. LncRNAs are essential to the process.

38
Q

When is imprinting patterns reset?

A

They are reset during gamete formation

39
Q

Why is pharmacoepigenetics studied?

A

It is known to cause epigenetic regulation of genes or epigenetic effects of drugs.

40
Q

Why is it important to study the epigentic regulation of genes?

A

Information can be used to increase the efficacy of drug treatment

41
Q

Why is it important to study the epigenetic effects of drugs?

A

New paradigms for the drug treatment

42
Q

How is global methylation effected in cancer?

A

Known that global DNA methylation is altered in tumour cells. This causes:

  • Hypermethylation of tumour suppressor genes
  • Hypomethylation of tumour activating genes
43
Q

Which enzymes are affected in tumour cells

A
  • DNMT3A and TET1/2
  • Histone Acetyltransferases
  • Histone Methyltransferases
  • Histone Kinases
  • Histone Readers
  • Histone Demethylases
    These are often mutated in tumour cells
44
Q

What is an example of a pharmacoepigenetic drug?

A

DNA methyl transferase inhibitors

  • 5-Azacytidine (Vidaza)
  • Myelodysplastic syndrome
  • Histone deactylase inhibitors
  • Romidepsin (Istodax)
  • Cutaneous T-cell lymphoma

Genomics (19 decks)

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