13 - Cancer Epigenetics Flashcards
DNA + protein (chromatin)
= chromosomes
Germ layers specified during development
- Ectoderm (outer layer)
- Mesoderm (middle layer)
- Endoderm (internal layer)
Epigenetics
Stable & heritable, yet reversible changes in the way genes are expressed without changing their original DNA sequence
Examples of epigenetic changes
- DNA methylation
- Histone modifications (acetylation/methylation)
Waddington landscape
A metaphor of development, in which valleys and ridges illustrate the epigenetic landscape that guides a pluripotent cell to a well-defined differentiated state, represented by a ball rolling down the landscape.
Epigenome remodeling during differentiation
- Lymphoid/myeloid development
- T helper differentiation
- Muscle stem cell differentiation
- Neural stem cell differentiation
Four different processes can alter gene transcription through changes in chromatin
- Post-translational modification of histone proteins
- Variant histones
- Chromatin remodelling
- DNA methylation
Charge of DNA
-
Charge of histones
+
Histone acetylation
- Occurs on the lysine residues of histone tails
- Neutralises the positive charge & decreases their affinity for DNA
- DNA is less tightly wound & permits transcription
Acetylated lysine residues
transcriptional activation (gene expression)
Deacetylated lysine residues
Transcription repression (gene silencing)
Histone acetylase (HAT)
Add acetyl groups
Histone deacetylase (HDAC)
Remove acetyl groups
Histones near active genes
Hyperacetylated
Epigenetic writers
Responsible for the addition of chemical
modifications
Epigenetic erasers
Catalyse the removal of covalent modifications
Epigenetic readers
Proteins with specific domains that recognize and bind to particular modifications
Methylation
Methylation → condensed chromatin → transcription repressed
Demethylation
Demethylation → expanded chromatin → transcription permitted
DNA methylation and age
Young = more methylation
Old = more demethylation
Leukaemia
Leukaemia arise from myeloid or lymphoid progenitor cells and are found in the bone marrow and blood
Lymphoma
Arise from lymphatic tissue occurring mainly in lymph nodes
Origins of cancer
- Environmental (smoking)
- Genetic
- Infectious disease
How many cancer driver genes identified
581
Genome-epigenome changes driving cancer
Many cancers show global hypomethylation and focal hypermethylation of unmethylated CpG islands
Example of epigenetic regulatory genes
that are significantly mutated in many sub-types of solid and hematological cancers
KMT2A-gene rearrangements
Presence of oncogene
Not necessarily lead to development of cancer because a functioning tumour suppressor gene
might prevent the cell from replicating.
TSG knockout
If a tumour suppressor gene is knocked out but there is no oncogene present, then the cell is unlikely to be immediately cancerous
Oncogene mutation
dominant gain-of-function mutations in proto - oncogenes
How do proto-oncogenes become oncogenes
When expressed at increased levels, resulting from either:
- Amplification leading to more copies of the gene
- Translocation to a more active promotor
- Mutation resulting in a fusion protein with oncogene activity
Writing agent drugs
Acetylases
Erasing agent drugs
Deacetylases
Reading agent drugs
Bromodomain
