Epigenetics and Cancer Flashcards
Define epigenetics
Factors causing a heritable change in gene expression in the absence of change in the DNA sequence itself.
What is a transcriptome?
What is a proteome?
What is a metabolome?
Collective pool of RNA
Collective pool of protein
Collective pool of metabolites
What is the epigenome very susceptible to?
Changes in environment
What are the 3 main epigenetic mechanisms?
DNA methylation at CpG dinucleotides
Histone modifications (acetylation etc)
Non coding RNAs (ncRNA)
What is DNA methylation at CPG nucleotides?
Methylation of cytosine at the 5th carbon
Occurs at CpG dinucleotides (cytosines located next to a guanine base)
Methylation of CPG nucleotides can influence DNA protein integrations, resulting in changes in gene expression.
What does DNA methyltransferase (DNMT) do?
How is this different to mutation?
What is the effect of this?
DNA methyltransferase (DNMT):
- Transfers methyl group from the substrate S-adenosylmethionine (SAM) to the 5th carbon position of a cytosine base located immediately next to a guanine base.
Different to mutation as the base has not been changed, just has the methyl group added.
Affects how the gene is expressed
How does DNA methylation at CpG nucleotides impact gene expression?
Promoter regions of genes tend to have more repeats of CpG nucleotides compares with the gene bodies. This because they regulate transcription of the gene which occurs via proteins binding to the promotor region of the gene.
If the DNA methyltransferase and substrate (SAM) are present, they methylate the CpG nucleotides which creates a barrier between the promotor region and the protein trying to bind. It can therefore not bind and the gene is not transcribed and becomes inactive.
(If the CpG nucleotides are not methylated, there is no inhibition and the genes are transcribed, therefore activated)
How might DNA methylation trigger formation of a cancer?
If a tumour suppressor gene becomes methylated, it can no longer be transcribed and the gene is no longer expressed, which can allow the growth of a tumour cell.
Oncogenes can become unmethylated and therefore be transcribed.
What are transposable elements?
How are they controlled?
How are they linked to increased disease with ageing?
What percentage of the human genome is transposable elements?
Sections of DNA that often originate from viruses.
They are able to move about in the genome therefore are unstable and linked to certain diseases.
They can cause mutations and change the sequence of a gene.
They are heavily methylated so in healthy individuals are not expressed. In ageing, they can lose their methylation and cause disease.
Around 55% of the human genome is transposable elements.
What are histone modifications?
Combination of chemical modifications of amino acids on histone tails which can impact gene expression.
What is the basic roles of histones?
To compact the DNA to allow it to fit into a cell.
They regulate gene expression
How do histones regulate gene expression?
Genes that are compacted tightly by histones are not easily transcribed as it is harder for transcription factors to bind. Therefore the positioning of histones along the DNA material either allows or inhibits the transcription of certain genes.
Histones have ‘tails’ which are not wrapped around DNA and are free. They are amino acids and are easily accessible by enzymes which can modify them e.g by adding functional groups which modifies the expression of the gene.
How does the modification of histone tails affect gene expression?
Which enzymes can be responsible for this?
Histones are positively charged, DNA is negatively charged which is why they are tightly compacted together.
Acetyl groups for example are negatively charged, so when added to a positively charged histone tail, the histone charge is neutralised, loosening its binding from DNA, allowing the transcription of the genes. The acetyl group can be added by histone acetyltransferase (HATs) for example.
Similarly, when an acetyl group is removed, the histones positive charge is increased and it binds more tightly to DNA, not allowing the genes to be transcribed or expressed. The acetyl groups can be removed by the enzyme histone deacetyltransferase (HDACs).
Which factors impact epigenetic modulation?
Diet
Exercise
Psychological state
Microbiome
Toxic chemicals (e.g. smoking)
Drugs
Disease exposure
Diurnal variation
What factors may speed up or slow the natural process of ageing?
Chemicals in the body that may remove the substrate needed for methylation- genes may become unmethylated therefore are transcribed and expressed.
