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SGUL - Genomics > The Epigenome > Flashcards

The Epigenome Flashcards

1
Q

Define what is meant by the Genome?

A
  • The complete set of genetic material in a cell
  • The DNA sequence that is present in a single full set of chromosomes
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2
Q

What is meant by the Nucleosome?

A

The Nucleosome is the Histone proteins and DNA that form the first level of packing

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3
Q

What is the packing solution?

A
  • Nucleosome are wound up to form 30 nm fibres
  • Fibres 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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4
Q

What’s are the two types of Chromatin?

A

Euchromatin and Hetero Chromatin

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5
Q

What is Euchromatin?

A
  • Gene rich
  • Transcriptionally active
  • Dispersed appearance
  • Unique DNA sequences
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6
Q

What is Hetero chromatin?

A
  • Gene poor
  • Less Transcriptionally active
  • Condensed Appearance
  • Repetitive DNA sequences
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7
Q

What is meant by the Epigenome?

A
  • The sum of all the heritable changes in the genome that do not occur in the primary DNA sequence and that affect gene expression
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8
Q

What does an Epigenetic change result in?

A

A Change in the phenotype but not in the genotype

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9
Q

Give an overview of the Epigenome

A
  • The Epigenome is central to the regulation of gene expression
  • Gene expression is regulated by DNA methylation and Histone modifications
  • X activation and imprinting are important Epigenetic mechanisms for controlling expression from groups of genes
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10
Q

What are Epigenetics used for?

A

Used to identify novel drug targets

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11
Q

What are some epigenetic mechanisms?

A
  • DNA Methylation
  • Histone modification
  • X-inactivation
  • Genomic Imprinting
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12
Q

Describe what DNA methylation is

A
  • In humans, it is the addition of a methyl group in the 5’ position of a cytosine
  • The reaction is catalysed by the DNA methyltransferase enzymes
  • Requires an S-Adenosyl Methionine to provide the methyl group
  • Occurs in the CpG dinucleotides in differentiated cells
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13
Q

How is DNA Methylation linked to gene expression?

A
  • DNA methylation turns transcription off by preventing the binding of transcription factors
  • DNA methylation pattern changes during development and are an important mechanism for controlling gene expression
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14
Q

What is Histone Modification?

A
  • The addition of chemical groups to the proteins that make up the Nucleosome
  • There are large numbers of known Histone modifications (>100) but many of them are unknown functions
  • There are a wide range of enzymes that can catalyse modification’s
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15
Q

What are some common modifications?

A
  • Methylation
  • Acetylation
  • Phosphorylation
  • Ubiquitination
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16
Q

What happens when amino acids are modified?

A
  • Amino acids can be modified and can have anywhere between 1-4 groups added
  • This gives a large number of modifications
  • Others are known but poorly understood
17
Q

What are Histone modifications names based on?

A

Based on 3 different factors:
- The Histone
- The amino acid
- The Actual modification

18
Q

What are the 3 types of Histone modifiers?

A
  • Writers
  • Erasers
  • Readers
19
Q

Give some examples of “writer” Histone modifiers

A
  • Histone Acetyltransferase - HAT1
  • Histone Methyltransferase - EHMT1
20
Q

Give some examples of “Erasers” Histone modifiers

A
  • Histone Deacetylase: HDAC1
  • Histone Demethylase: KDM1
21
Q

Give some examples of “Reader” Histone modifiers

A
  • Bromodomain and extra-terminal (BET) proteins: BRD2
  • Chromodomain proteins: CBX1
22
Q

What are the roles of Histone modifications?

A
  • Histone acetylation at Lysone residues relaxes the chromatin structure, by reducing positive charge on the Histones and makes it accessible for transcription factors
  • Histone methylation is more complex and can repress or activate transcription depending on where it occurs
  • Histone modifications can occur concurrently and so their effects will interact
23
Q

What is X-Inactivation?

A
  • The inactivation of one of the 2 X chromosomes in every somatic cell in females
  • This is needed as the Y chromosome has virtually no genes, so there is only one group of each chromosome gene in males (Hemizygosity)
24
Q

What does X Inactivation ensure?

A

Ensures that every somatic cell in all humans has the same number of active copies of every gene

25
Q

Describe how X inactivation works (PART 1)

A
  • The Xist gene is transcribed as a long noncoding RNA (lncRNA) from the X-inactivation centre (Xic) and binds all over the X-chromosome
  • Histone acetylation removed and histone and DNA methylation occurs
26
Q

Describe how X inactivation works (PART 2)

A
  • 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
27
Q

Give an example of X inactivation

A
  • All tortoiseshell cats are female
  • Tortoiseshell cats have one X with an orange fur allele and one X with a black fur allele
  • Random X inactivation results in patches of orange and black fur
28
Q

What is Genomic Imprinting?

A
  • It is the selective expression of genes related to the paternal origin of the gene copy
  • Every autosomal gene has one Paternal and one Maternal copy
29
Q

How are imprinted genes usually found?

A

Imprinted genes tend to be found in clusters

30
Q

How common are imprinted genes?

A

Not very common. Very few imprinted genes (~250)

31
Q

What is imprinting mediated by?

A

By the Imprinting control regions (ICRs)

32
Q

How does imprinted genes work?

A
  • One copy is silenced by DNA methylation catalysed by DNMT3a and Histone methylation leading to inactivation
  • LmcRNAs are essential to the process
  • Imprinting patterns are reset during gamete formation
33
Q

What are the two general mechanisms for epigenetic modification?

A
  • DNA methylation
  • Histone modification
34
Q

What are the two specific mechanisms for epigenetic modification?

A
  • X inactivation
  • Genetic Imprinting
35
Q

CANCER EPIGENETICS
Where is the global DNA methylation altered in tumour cells?

A
  • Hypermethylation of tumour suppressor genes
  • Hypomethylation of tumour activating genes
36
Q

Where are epigenetic enzymes often mutated?

A

In tumour cells

37
Q

Give some examples of these Epigenetic enzymes

A
  • Histone Methyltransferases
  • Histone Acetyltransferases
  • Histone Kinases
  • Histone readers
  • Histone Demethylases
38
Q

Give some examples of Pharmaco - Epigenetic drugs

A

DNA Methyl Transferase Inhibitors
- 5 - Azacytidine (Vidaza)
- used to Treat Myelodysplastic syndrome

39
Q

Give some examples of Pharmaco - Epigenetic drugs

A

Histone Deacetylase Inhibitors
- Romidepsin (Istodax)
- Used to treat Cutaneous T-cell lymphoma

SGUL - Genomics (21 decks)

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