The Epigenome Flashcards
Define the Genome.
DNA sequence that is present in a single full set of chromosomes
What is the First level of DNA packing?
nucleosomes
-histone proteins bound to DNA
What is chromatin?
organisation of DNA in nucleosomes:
> Euchromatin: gene-rich, transcriptionally active, dispersed appearance, unique DNA sequences
> Heterochromatin: gene-poor, less transcriptionally active, condensed appearance, repetitive DNA sequences
Describe the Packing Solution of Genome.
· Nucleosomes are wound up to form 30nm fibres
· Fibres are then wound up further with scaffold proteins to generate higher-order structures
· Chromosomes are the most densely packed form of genomic DNA
What is the epigenome?
the sum total of heritable changes in the genome that do not occur in the primary DNA sequence which affect gene expression
*epigenetic change results in a change in phenotype but not in genotype
What are the Types of epigenetic mechanisms?
DNA methylation
Histone modification
X-inactivation
Genomic imprinting
What is DNA methylation?
DNA methylation is the addition of methyl groups (-CH3) in the 5’ position of a cytosine
- doesn’t happen at every cytosine in DNA
- occurs in CpG dinucleotides in differentiated cells
What is the Enzyme which catalyses DNA methylation?
DNA methyltransferase
-DNMT1, DNMT3a, DNMT3b
What provides the methyl group for DNA methylation?
S-Adenosyl Methionine (SAM)
-becomes S-Adenosyl Homocysteine (SAH) due to loss of methyl group
How does DNA methylation affect gene expression?
turns transcription off by preventing the binding of transcription factors
What is DNA demethylation?
removal of the methyl group, converting the nucleotide back to cytosine via a number of intermediates (not directly back to cytosine):
>5-hydroxymethylcytosine
>5-formylcytosine
>5-carboxycytosine
What is histone modification?
addition of chemical groups to histone proteins
Examples:
- acetylation
- methylation
How are histone modifications named?
Modifications are named based on the histone it affects, the amino acid and the actual modification.
For example, a modification called H3K4Me3 means that it is a modification on Histone 3, the Lysine at position 4 and is tri-methylated.
What are the enzymes that add modifications to histone tails called?
WRITERS
Histone acetyltransferase (HAT1) Histone methyltransferase (EHMT1)
What are the enzymes that remove modifications to histone tails called?
ERASERS
Histone Deacetylase (HDAC1) Histone Demethylase (KDM1)
Enzymes which bind to histone modifications and alter gene activity and protein production are known as…
READERS
Bromodomain and Extra-terminal (BET) proteins- BRD2
Chromodomain proteins -CBX1
What are the Effects of histone modification?
Histone acetylation at Lysine residues relaxes chromatin structure, making it more 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 can interact or modify each other
What is X-inactivation?
inactivation of one of the two X chromosomes in every somatic cell in females
What is the Importance of X inactivation?
ensures that every somatic cell in all humans has the same number of active copies of every gene (because Y chromosome in males has virtually no genes)
What are the Steps of X inactivation?
· The Xist gene is transcribed as a long non-coding RNA (lncRNA) from the X-inactivation centre (Xic) and binds all over the X-chromosome to regulate gene expression
·Histone acetylation is removed and histone and DNA methylation occurs to inactivate that chromosome
·Inactive X-chromosome is heterochromatic and is referred to as Barr body
How to prevent other X chromosome from inactivating?
·You don’t want both X chromosomes to be inactive and so one chromosome transcribes Tsix gene in the opposite direction from a reverse sequence long noncoding RNA and antagonises Xist RNA to keep one X active.
What is genomic imprinting?
Genomic imprinting refers to selective expression of a gene depending on whether it was inherited from the male parent or the female parent.
Where are imprinted genes found?
in clusters in autosomes
What is imprinting mediated by?
imprinting control regions (ICRs), which silence genes near them using DNA methylation and histone methylation
- one copy is silenced by DNA methylation catalysed by DNMT3s and histone methylation leading to inactivation
- long noncoding RNAs (lncRNAs) are essential to the process (like X-inactivation)
- imprinting patterns are reset during gamete formation
What are Pharmacoepigenetics?
studies the underlying epigenetic patterns that lead to variation in an individual’s response to medical treatment.
What is the pharmacoepigenetics field split into?
Two areas:
- Epigenetic regulation of genes
- Epigenetic effect of drugs
Describe epigenetics in cancer.
· Global DNA methylation is altered in tumour cells
>Hypermethylation of tumour suppressor genes (reducing gene expression)
>Hypomethylation of tumour activating genes (increasing gene expression and favouring cancer formation)
Give some Epigenetic enzymes in tumour cells.
epigenetic enzymes are often mutated in tumour cells:
- DNMT3a and TET1/2
- Histone Acetyltransferases
- Histone Methyltransferases
- Histone Kinases
- Histone Readers (acetyl/methyl/phosphoryl)
- Histone Demethylases
Give some Pharmacoepigenetic drugs in cancer treatment.
DNA Methyltransferase Inhibitors
> 5-Azacytidine (Vidaza)
> Treatment of Myelodysplastic syndrome
Histone Deacetylase Inhibitors
> Romidepsin (Istodax)
> Treatment of Cutaneous T-cell Lymphoma
