Mutations, Gene expression, Cancer

• Only stem cells can divide by mitosis
• Totipotent cells - can differentiate into any cell type in the body e.g. zygotic cells
• Pluripotent - can differentiate into most cell types
• Multipotent - can differentiate into some cell types e.g. stem cells in bone marrow
• Unipotent - can only give rise to one type of cell e.g. cardiomyocyte
• Differentiation of stem cells is determined by gene expression
• Most of a cell's DNA is not translated and these genes are not expressed
• Ethical concerns of using stem cells:

  • May be unethical to use embryos
  • Embryos may have no moral rights or are not really humans
  • Stem cell treatments tested on animals
  • Patients need to give consent for cells to be used
• Promoter region - the base sequence found upstream of a gene that controls the expression of that gene
• Transcription factor - proteins, when activated, bind to the promoter region stimulation RNA polymerase to begin transcription
• Example of a transcription factor is oestrogen
• Activation of transcription - oestrogen:

  1. Oestrogen is lipid-soluble so diffuses through phospholipid bilayer
  2. Diffuses through nuclear envelope
  3. Binds to oestrogen receptor
  4. Changes the tertiary structure of oestrogen receptor
  5. Releases transcription factor
  6. Transcription factor binds to DNA at the promoter region
  7. Stimulates RNA polymerase to transcribe the gene
• If translation needs to be reduced, these are used:

  • miRNA
  • siRNA
• Control of translation - iRNA:

  • miRNA/siRNA binds to protein to form a complex
  • Called an RNA-induced silencing complex (RISC)
  • RISC inhibits gene expression by binding to complementary mRNA
  • mRNA is then hydrolysed by an enzyme (mRNA cut into fragments)
  • RISC may also inhibit the initiation of ribosomal translation (ribosome cannot attach to mRNA, mRNA hydrolysed)
• If siRNA or miRNA introduced translation does not take place, the polypeptide is not produced and the expression of the gene has been silenced
• Protein can still be produced in smaller quantities because not all of the mRNA has been destroyed
• Epigenetics - the study of how environmental factors can alter gene expression without changing the DNA sequence
• Inheritable changes can inhibit transcription by:

  • Increased methylation of DNA
  • Decreased acetylation of histones
• Methylation of DNA:

  • Methyl group added to cytosine base (CpG)
  • Methyltransferase catalyses the methylation reaction
  • Methylation of CpG 'silences' the affected genes by preventing transcription factors from binding to the promoter
  • Prevents RNA polymerase activation and inhibits transcription
• Acetylation of histones:

  • Acetylation of histones makes them loosely packed so DNA is less condensed
  • When unwound, promoter regions are exposed and transcription factors are able to bind
  • RNA polymerase can bind to the target gene and transcribe
• DNA of gene (inaccessible)

  • Decreased acetylation - histones
  • Increased methylation - DNA
  • Tightly packed - DNA-histone complex
  • Heterochromatin - chromatin
  • Transcription factors have no access
  • Gene - inactive
• DNA of gene (accessible)

  • Increased acetylation - histones
  • Decreased methylation - DNA
  • Loosely packed - DNA-histone complex
  • Euchromatin - chromatin
  • Transcription factors have access
  • Gene - active
• Malignant tumours - fast-growing tumours, non-capsulated and they do metastasise (spread)
• Benign tumours - slow-growing tumours, surrounded by a capsule and do not metastasise (no spread)
• Rate of cell division controlled by:

  • Proto-oncogenes (stimulates cell division)
  • Tumour suppressor genes (slows cell division)
• Changes to tumour suppressor gene:

  • Increased methylation -> increases rate of cell division
  • Increased acetylation -> decreases rate of cell division
• Epigenetic changes to oncogene:

  • Decreased methylation -> increases rate of cell division
  • Decreased acetylation -> decreases rate of cell division
• If a mutation occurs in a proto-oncogene, it changes to become an oncogene. This results in permanent uncontrolled cell division.
• If a mutation occurs in a tumour suppressor gene, the gene is inactivated and cell division is not inhibited - increases rate of cell division
• How methylation of a tumour suppressor gene causes cancer:

  • Methylation so no translation of gene
  • Protein that prevents cell division is not produced
  • No prevention of cell division
• How increased methylation leads to cancer:

  • Methyl groups added to tumour suppressor gene
  • Increased rate of cell division
  • Due to tumour suppressor gene being silenced and not transcripted
• How both types of tumours can cause harm:

  • Pressure on other organs
  • Damages organ involved
• Family history of cancer may lead to increased risk of cancer due to genetic pre-disposition
• How altered DNA may lead to cancer:

  • DNA altered by mutation
  • Changes base sequence of the tumour suppressor gene
  • Changes base sequence of gene controlling cell division
  • Changes protein structure
  • Produces protein that cannot inhibit cell division
• How examining mRNA identifies cancer present:

  • mRNA base sequence will change
  • Different DNA structure
  • Tumour suppressor gene inactive
• Substitution mutation - Replacement of one base for another
• Define epigenetics:

  • Heritable changes in gene function
  • Without changes to the base sequence of DNA