The epigenome Flashcards
Genome
- 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
Packing solution
Histones
Nucleosomes
Fibres and higher structures
Chromosomes are the most densely packed form of genomic DNA
Epigenome
- 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
Epigenetic mechanism
- DNA Methylation
- Histone modification
- X-inactivation
- Genomic Imprinting
DNA methylation
- 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
DNA methylation enzymes
DNMT1, DNMT3a and DNMT3b
TET
Ten-Eleven translocation enzyme
TDG
Thymine DNA glycosylase
BER
Base excision repair
2-OG
2-oxoglutarate
DNA methylation and gene expression
- 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
Histone modifications
- 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
Common histone modifications
- Methylation
- Acetylation
- Phosphorylation
- Ubiquitination
H3K4Me3
Histone 3, the Lysine (K) at position 4 is tri-methylated
HAT1
Histone Acetyltransferase
EEHMT1
Histone Methyltransferase
HDAC1
Histone deacetylase
KDM1
Histone demethylase
Role of histone modifications
- 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
X-inactivation pt 1
- 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
X inactivation pt 2
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
Genomic imprinting
- 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
ADME
Absorption
Distribution
Metabolism
Excretion
Enzymes related to mutated tumour cells
DNMT3A and TET1/2 Histone Acetyltransferases Histone Methyltransferases Histone Kinases Histone Readers (acetyl/methyl/phosphoryl) Histone Demethylases