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The epigenome Flashcards

1
Q

Genome

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

• Histone proteins and DNA form the first level of packing – the nucleosome

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2
Q

Packing solution

A

Histones
Nucleosomes
Fibres and higher structures
Chromosomes are the most densely packed form of genomic DNA

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3
Q

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
  • An epigenetic change results in “A change in phenotype but not in genotype”
  • The epigenome is central to the regulation of gene expression
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4
Q

Epigenetic mechanism

A
  • DNA Methylation
  • Histone modification
  • X-inactivation
  • Genomic Imprinting
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5
Q

DNA methylation

A
  • DNA methylation in humans is the addition of a methyl group in the 5’ position of a Cytosine
  • This is catalysed by DNA methyltransferase enzymes
  • It requires S-Adenosyl Methionine to provide the methyl group
  • In differentiated cells it occurs in CpG dinucleotides
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6
Q

DNA methylation enzymes

A

DNMT1, DNMT3a and DNMT3b

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7
Q

TET

A

Ten-Eleven translocation enzyme

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8
Q

TDG

A

Thymine DNA glycosylase

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9
Q

BER

A

Base excision repair

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10
Q

2-OG

A

2-oxoglutarate

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11
Q

DNA methylation and gene expression

A
  • In general, DNA Methylation turns transcription off by preventing the binding of transcription factors
  • DNA methylation patterns change during development and are an important mechanism for controlling gene expression
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12
Q

Histone modifications

A
  • This is the addition of chemical groups to the proteins that make up the nucleosome
  • There are a large number of known histone modifications (>100) and many are of unknown function
  • Large range of enzymes catalyse modification
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13
Q

Common histone modifications

A
  • Methylation
  • Acetylation
  • Phosphorylation
  • Ubiquitination
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14
Q

H3K4Me3

A

Histone 3, the Lysine (K) at position 4 is tri-methylated

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15
Q

HAT1

A

Histone Acetyltransferase

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16
Q

EEHMT1

A

Histone Methyltransferase

17
Q

HDAC1

A

Histone deacetylase

18
Q

KDM1

A

Histone demethylase

19
Q

Role of histone modifications

A
  • Histone acetylation at Lysine 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
20
Q

X-inactivation pt 1

A
  • This is the inactivation of one of the two X chromosomes in every somatic cell in females
  • This is needed as the Y chromosome has virtually no genes, so there is only one copy of each X chromosome gene in males (hemizygosity)
  • X-inactivation ensures that every somatic cell in all humans has the same number of active copies of every gene
21
Q

X inactivation pt 2

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
• 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

22
Q

Genomic imprinting

A
  • Imprinting is the selective expression of genes related to the parental origin of the gene copy
  • Every autosomal gene has one paternal and one maternal copy
  • Imprinted genes tend to be found in clusters
  • There are very few imprinted genes (~250)
  • Imprinting is mediated by imprinting control regions (ICRs)
  • One copy is silenced by DNA methylation catalysed by DNMT3a and histone methylation leading to inactivation
  • LncRNAs are essential to the process
  • Imprinting patterns are reset during gamete formation
23
Q

ADME

A

Absorption
Distribution
Metabolism
Excretion

24
Q

Enzymes related to mutated tumour cells

A 
DNMT3A and TET1/2
	Histone Acetyltransferases
	Histone Methyltransferases
	Histone Kinases
	Histone Readers (acetyl/methyl/phosphoryl)
	Histone Demethylases
25
Q

Cancer and epigentics

A

Global DNA methylation is altered in tumour cells
Hypermethylation of tumour suppressor genes
Hypomethylation of tumour activating genes
Epigenetic enzymes are often mutated in tumour cells

26
Q

Pharmacoepigenetic drugs

A 
•	DNA Methyl Transferase Inhibitors
	5-Azacytidine (Vidaza)
	Myelodysplastic syndrome
	Histone Deacetylase Inhibitors
	Romidepsin (Istodax)
	Cutaneous T-cell lymphoma
	Seven drugs FDA-approved so far

Genomics (19 decks)

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