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Developmental genetics and embyronal cancer > Epigenetic regulation > Flashcards

Epigenetic regulation Flashcards

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1
Q

What is epigenetics? Give 3 examples?

A

altering of gene expression without changing the primary DNA structure
- DNA methylation
- histone modifications
- non-coding RNAs

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2
Q

What is the role of epigenetics in normal cells? Give 3 examples

A
  • the compartmentalisation of a complex genome into active and repressed regions
  • silencing of parasitic sequences
  • X inactivation
  • imprinting
  • mainly controlled by DNA methylation and histone modification
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3
Q

What is the epigenome

A

the epigenetic code of the DNA

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4
Q

What is histone modification?

A

molecules attach to histone tails and affect chromatin condensation and DNAs ability to be transcribed

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5
Q

What is the basic mechanism underlying DNA methylation?

A
  • methyl groups added to cytosines make them into 5-methylcytosine
  • catalysed by DNMTs
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6
Q

How are methyl marks removed? how is it different to addition?

A
  • multiple steps and slower
  • TET enzymes drive multiple steps where the cytosine has multiple formations before going back to normal
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7
Q

How is DNA methylation controlled?

A
  • formed at gametogenesis and maintained through divisions
  • DNMT1 is a maintenance DNMT that maintains methyl marks
  • DNMT3A/B/L are de novo DNMTs that don’t require a template to add new methyl groups
  • TET genes involved in demethylation
  • KOs found role of DNMTs in mice that are embryonic lethal and alter methylation and imprintation
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8
Q

How can DNMTs be altered in cancer?

A
  • very rarely mutated
  • often overexpressed
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9
Q

Where does most DNA methylation occur in mammals?

A
  • at CpG islands (some non CpG especially in ESCs)
  • 50% of genes have them
  • stretches of DNA with CG content over 60%
  • usually demethylated and methylation is associated with cancer
  • non CpG methylation occurs in ESCs and not fully understood
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10
Q

Describe a method that can be used to test for methylation

A
  • purify DNA and treat with bisulphide
  • unmethylated cytosines will be deaminated into uracils
  • methylated cytosines will remain to be measured
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11
Q

Name 3 ways methylation inhibits transcription

A
  • directly causing steric hindrance and stopping TF binding
  • indirect effects via chromatin remodeling
  • boundary elements
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12
Q

How can methylation affect chromatin to inhibit transription?

A

when methylation occurs, methyl-binding domain proteins can recognise methyl groups and complex with histone deacetylase proteins and deacetylase the histones, pulling the DNA closer to further repress transcription

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13
Q

What are boundary elements?

A
  • markers that help to control the boundaries between methylated and unmethylated regions
  • can affect the action of promoters
  • helps to regulate gene transcription
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14
Q

How are histone modifications controlled?

A
  • change throughout development
  • marks are added and removed by enzymes such as HATs and HDACs
  • regulated by readers, writers and erasers
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15
Q

Give an example of histone mark readers

A
  • bromodomains
  • recognise marks on the histones and signal for downstream TF and chromatin regulation
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16
Q

Give an example of histone erasers

A
  • TETs perform demethylation
17
Q

Give an example of histone writers

A
  • HDACs, HATs
  • methyltransferases, demethylases
18
Q

What are the 2 possible mechanisms by which DNA methylation and histone modificatoin may interact?

A
  • DNA methylation driving histone modification
  • histone modification driving DNA methylation
  • evidence for both has been found
19
Q

How might DNA methylation direct histone modifications?

A
  • DNA methylated regions recruit methyl-CpG-binding proteins and histone deacetylase
  • this recruits histone methyltransferases that methylate the histones and stabilise the inactive chromatin
20
Q

How might histone modifications direct DNA methylation?

A
  • inactive chromatin undergoes DNA replication
  • histones recruit HP1 which recruits DNA methyltransferases to maintain DNA methylation throughout division
21
Q

Does histone methylation have activating or repressing effects?

A
  • both
  • H3K4 = activating
  • H3K9 or H3K27 = repressive
22
Q

How does DNA/histone methylation co-operation turn off pluripotency genes in development?

A
  • G9a histone methyltransferase induced H3K9me2
  • also recruits DNMTs to induce DNA methylation
23
Q

What are chromsome domains?

A
  • modular structures in chromatin that correlate with epigenetic marks
  • each have distinct tsructural and functional properties
  • for example polycomb domains control Hox gene silencing in drosophila
24
Q

How do epigenetic changes lead to X-inactivation

A
  • long non-coding RNA Xist binds the chromosome to be inactivated
  • DNA is highly methylated with repessive histone methyl marks too (H3K9me2, H4K27me3)
  • Xist can attract chromatin-modifying complexes such as polycomb to mediate inactivation
25
Q

How do epigenetic changes lead to inactivation of parasitic sequences?

A
  • 50% of the human genome is made of damaging repeats such as transposons that can insert into other genes
  • most 5-methylcytosine is found at these sites and transposon promoters are inactivated
  • prevents unwanted transcription
26
Q

What is genomic imprinting?

A
  • mule female horse, hinny female donkey - parental origin of genes are different
  • imprinted genes only express one allele
  • phenotype dependent on parental origin
  • resets on passage through the germline
27
Q

What is the life cycle of DNA methylation in imprinting ?

A
  • at the germline, de novo DNMTs add methyl marks
  • these are maintained through cell division by maintenance DNMTs
  • continues until gametogenesis where TETs remove methyl marks and new ones are applied
28
Q

What are the basic characteristics of imprinted genes?

A
  • only expressed on one allele
  • often in clusters with imprinting control regions within them
  • antisense and ncRNAs are common
  • different methylation patterns on each allele
29
Q

What are two human tumours that can arise from incorrect imprinting?

A
  • Wilm’s tumour from incorrect WT1 imprinting (leads to poor MET)
  • ovarian teratomas caused by lac of paternal imprinting
30
Q

Give an example of a genomic imprinting locus.

A
  • IGF2 encodes fetal growth factor and is only expressed on the paternal allele
  • H19 encodes an untranslated RNA that appears to act as a tumour suppressor and is only expressed on the maternal allele
31
Q

How do IGF2 and H19 interact in genomic imprinting on the paternal allele?

A
  • on the paternal allele the IGF2 promoter interacts with an enhancer downstream of H19
  • extensive DNA methylation of the boundary element between IGF2 and H19 means that CTCF cant bind and this can happen
  • 2 alleles like this can lead to wilms tumour
32
Q

How do IGF2 and H19 interact in genomic iprinting on the maternal allele?

A
  • no hypermethylation of the boundary element
  • CTCF can bind here and create a boundary that stops the IGF2 promoter from accessing the promoter
  • allows H19 to use it instead
  • two alleles like this can lead to dwarfism
33
Q

What are epimutations?

A
  • mutations that can interfere with the loss of boundary elements
  • seen in Wilm’s tumour if IGF2 is overexpressed on both alleles
  • mutation that enhances the boundary element instead has 2 H19 alleles and leads to growth failure - silver-russell dwarfism)
34
Q

What are two theories on why genomic imprinting evolved?

A

Haig theory - imporinting lessens conflict between patnerla and maternal genomes by allowing a mixture to be expressed
Barlow theory - methylation developed as a defense against foreign DNA and was evolved for control of development

Developmental genetics and embyronal cancer (17 decks)

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