Epigenetic's Flashcards
what is the definition of the epigenome
Changes in the organisms caused by chemical modification of DNA which alter the gene expression rather than alteration of the genetic code
- Epigenetics encompasses all processes that lead to heritable change in gene expression as cell divide, it does not alter the DNA sequences and these marks do not change the DNA sequences but instead change the way cells use instructions encoded by DNA
what influences the epigenome
- Internal – pre-natal development
- External – environmental exposures and disease
what is the difference between the genome and epigenome
- Genome is the complete set of genes, genetic material present in the cell
- the epigenome are the parts of the genome that are actually used, this is gene silencing versus gene expression, turn of genes that we don’t need
- The genome is static but the epigenome is flexible
- There are changes with age the interaction in the environment that starts before conception and happens throughout life
give some examples of epigenetic influences
- diet
- drugs alternative or abusive
- financial status
- smoking
- disease exposure
- alternative medicine
- exercise
- social interactions
- psychological state
describe your epigenetic life (SEE IF WE NEED THIS)
- preconception - tags are passed on from parents
- embryo - maternal nutrition provides epigenetic support
- infancy - maternal nutrition provides epigenetic support
- childhood
- adolescence
- early adult
- adult
- maturity
describe the epigenetic drift
- These changes can be subtle but there cumulative effect makes them difficult to predict in the final outcome
So..
Small epimutations can be tolerated by cells but once the deregulation reaches critical threshold this means that the cells no longer function
The phenotype outcome depends on the overall effect of the series of pre and post natal impacts of pre-epimutation
Only some individuals which are predisposed will reach the threshold of epigenetic deregulation that causes changes in the phenotype
what can reverse the epigenetic drift
- dietary restrictions
- reduce calorie diet linked to increased life span by decreasing the epigenetic drift
- Works by maintaining degree of methylation of DNA – methylation drift
Define epigenetic’s
the study of heritable changes in gene expression that occur without an alteration in the DNA sequence
What does it mean when the DNA is marked
- When epigenomic compounds attach to DNA and modify its function the genome is marked
- The marks do not change the DNA sequence but instead change the way cells use instructions encoded by DNA
what does epigenetic allow an organism to do
- Epigenetic inheritance allows an organism to continually adjust to the environment while adjusting the gene expression and not changing the genetic code
- Means that parents experiences are inherited by the next generations without passing it through DNA, basically the alterations are passed on but the DNA itself remains unchanged
describe twins as an example of epigenetic’s
- As many as 1;20 carries the mutant gene fusion- acute lymphoblastic leukaemia which often develops spontaneously from fusion of two genes
- Needs to have a 2nd trigger, chemical pollutants and infection
what does the barker hypothesis propose
- Proposes the idea that the origins of chronic diseases in adults begin in the uterus
- The environment that surrounds a foetus in utero affects their risk of developing disorders and conditions in later life
what is the genome
the genome is the complete set of genes and genetic material that is present in cells and organisms
- about 3 billion base pairs in humans
describe what the barker hypothesis links
- It links intrauterine growth retardation, low birth weight, and premature birth to hypertension, coronary heart disease and diabetes causally
- Low availability of nutrients during prenatal stage followed by improvement in nutritional availability in childhood causes increased risk of metabolic disorders, this is because the fetes expects to have a poor nutrimental diet
- Such as Diabetes type II, obesity, coronary heart disease
what are the 4 types of epigenetic mechanisms
- DNA methylation – cytosines
- Micro and small RNAs
- Histone modifications
- Chromatin architecture
describe the process of methylation
- There is an addition of a methyl group to cytosine the cytosine must be adjacent to guanine
- Catalysed by DNA methyltransferase (DNMTs)
- Methyl groups stop RNA polymerase II decreasing the transcription of the gene, therefore it silences the gene as it crowds out the RNA polymerase
- The methylation interferes with the binding of transcriptional activators to the promoter regions of the genes
- CpG islands (cytosine, phosphate, guanine) islands are the short sequences of DNA in which the frequency of CG is higher than other regions
- These are found in the promoter region where transcription is initiated, during these locations CG is not normally methylated
methylation patterns are….
tissue specific and heritable
what are the 4 main types of histone post translational modifications
- Acetylation(addition of the acetyl group)
- Methylation (addition of methyl group)
- Phosphorylation (addition of phosphate group
- Ubiquitylatin (addition of ubiquitin which marks proteins for degradation)
where does the histone post translational modification usually take place
usually present on lysine
what do the histone post translational modifications usually bind to
bind to the tails that stick out of histone proteins on lysine
what are the active gene and repressed genes
- Active genes – H3K4me3, H3K6me3
- Repressed genes – H3K27me3, H3K9me2/3
what enzymes catalyse histone modification
Histone acetylene (HAT) Histone deacetylase (HDAC)
Describe HAT and HDAC
- Histone acetylase (HAT)- Associated with open accessible DNA –catalyses the transfer of the acetyl unit to lysine in the histone therefore the promoter is more accessible for transcription and therefore transcription is activated
- Histone deacetylase (HDAC) – associated with closed inaccessible DNA – remove acetyl unit from the lyseine resulting in closed chromatin, and makes the promoter less accessible therefore transcription is repressed
describe chromatin archiecture
- This is a change in histone shape which alters the contact between DNA and histones
- This requires ATP which is needed for remodelling
- Structure of the nucleosome core is altered itself
what are the several mechanisms of chromatin remodelling
- Sliding
- Ejection
- H2A-H2B dimer ejection
- H2A-H2B dimer replacement
- Unwrapping
describe how micro and small RNAs work
- Micro RNA(miRNA) binds to mRNA at a complementary sequence
- This prevents the ribosome from attaching to the mRNA and thus blocks translation
- miRNA can also induce cleavage/degradation of mRNA
what do HDAC inhibitors do
- they inhibit the deacetylase enzyme so stop the acetyl units from being removed therefore there is an open relaxed chromatin
- HDAC inhibitors are used to increase gene transcription for some genetic conditions
- They can also modify epigenetic changes
- they are being used in clinical trials for acute myeloid leukaemia in combination with cytarabine and idarubicin
name some epigenetic therapies
HDAC inhibitors
DMT inhibitors
Non-coding RNA
osteopathic manipulation
what are methylation pattern linked to
they are linked to the control of gene expression and maintenance of chromosomal integrity
describe how hypomethylation leads to cancer development
- Normal genome is usually hypermethylated and stable
- Genome wide hypomethylation occurs with ageing and tumorigenesis
- Allows G4 DNA motif formation – this is with guanine rich sequences give a loose DNA structure which then allows them to be mutated, they are found in the promoter region in 70% of the genes
what is genetic imprinting
- Imprinting is the preferential expression of either the paternally or maternally inherited allele
describe how imprinting works
- If the allele is inherited from the father is imprinted it is silenced so only the allele from the mother is expressed
- This happens through Differential DNA methylation and histone methylation and acetylation of parental or maternal allele during gametogenesis
- Many imprinted gene associated with embryonic growth development, feeding, motivated behaviours, parental bias
what does parental imprinting want
- Parental imprinting favours larger offspring – it is in the interest of the father’s genes to produce larger offspring that will carry their genes into the next generation
what does maternal imprinting want
- Maternal imprinting favours small offspring, while it is best for all the mother genes if all the offspring survive to adulthood and reproduce to carry their genes into the next generation
what are the imprinting related disorders
Prader-willi and Angelman syndrome
what is prader-wili and angel man syndrome caused by
both caused by a deletion of a segment of chromosome 15
describe what happens in Prader-Wili
- paternal copy is deleted therefore only maternal genes are present,
this causes … - language
- motor
- developmental delay - excessive weight gain
describe what happens in angle man syndrome
- delete the maternal copy, this causes.... - severe mental retardation - happy demeanour - non-verbal
what does histone 1 do
linker histone which is involved in chromatin compaction and keeps DNA in place – locks DNA into place on outside
describe what DMT inhibitors do
- 5-azacytidine and 5-aza-20-deoxycytidine FDA approved for various forms of cancer
describe what non coding RNA does
- Difficult to deliver si and miRNAs
describe what osteopathic manipulation does
- Alter the environment and will influence genes and epigenetic environment
What are the 4 types of epigenetic mechanisms are are they silencing or promoting
- DNA methylation - silecing
- micro and small RNAs - predominantly silencing
- histone modifications - silencing or promoting
- chromatin architecture - silencing or promoting
How does methylation work
- There is an addition of a methyl group to cytosine the cytosine must be adjacent to guanine
- Catalysed by DNA methyltransferase (DNMTs)
- Methyl groups stop RNA polymerase II decreasing the transcription of the gene, therefore it silences the gene as it crowds out the RNA polymerase
