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MCB 2020 > 2.8 Epigenetics > Flashcards

2.8 Epigenetics Flashcards

1
Q
A
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2
Q

What is epigenetics?

A

Epigenetics is the study of changes in gene expression that occur without changes in DNA sequence.

Epigenetic changes are mitotically heritable

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3
Q

In what way can epigenetic modifications be reset?

A
  • Some epigenetic marks around implantation will persist for the entire lifetime
  • Germ cell and early embryonic development is where epigenetic marks are removed (break in the cycle)
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4
Q

Name the five epigenetic alterations

A
  1. DNA methylation
  2. Post translational histone modification
  3. Non coding RNAs
  4. Histone Variants
  5. Nucleosome remodelling/chromatin remodelling
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5
Q

Where does DNA methylation occur

A
  • At CpG dinucleotides in mammals, regions where C is followed by G base
  • A 5-methyl group is added
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6
Q

How does DNA methylation occur?

A
  • DNA methylation is laid down by de novo methyltransferases, DNMT3A and DNMT3B in mammals
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7
Q

How is DNA methylation symmetrical?

A
  • The new daughter strand of DNA (green) is not methylated
  • Because it is semi conservative you still have one strand with methylation
  • Maintenance DNMT1 lays down methylation on the other strand, recognising hemi methylated DNA
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8
Q

Apart from CpG islands where else does DNA methylation occur?

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9
Q

What is ICF syndrome?

A
  • Immunodeficiency, Chromosomal instability and Facial Anomolies syndrome
  • Very rare, autosomal recessive disorder with variable phenotypes
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10
Q

What causes ICF syndrome?

A
  • Mutation in DNA methyltransferase 3B (DNMT3B)
  • Hypomethylation of a small amount of the gemone in patients - not enough methylation
    • Pericentromeric repeats at centromeres of chromosome 1, 9, 16 related to chromosomal instability
    • Hypomethylation of CpG islands on inactive X chromosome in females, Y chromosome in males
    • Some other genes, related neurogenesis, immune funciton, craniofacial patterning, which all relate to phenotypes in patients
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11
Q

When does DNA demethylation happen?

A
  • It is mitotically heritable, due to action of maintenance methyltransferase DNMT1
  • DNA demethylation is shown to occur in early development, in primordial germ cell development and at later specific stages of differentiation
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12
Q

How is DNA demethylation achieved?

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13
Q

In what ways can DNA methylation cause silencing?

A
  • It can interfere with transcription factor binding
  • Result in the binding of methyl-CpG binding proteins which recruit other factors that alter chromatin state
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14
Q

Where do histone tail modifications occur?

A
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15
Q

What is histone acetylation?

A
  • Acetylation is correlated with gene activity, partly due to reduced positive charge of histone.
  • Not mitotically heritablem not strictly epigenetic, chromatin mark
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16
Q

What is histone methylation?

A
  • Histone methylation does not alter the charge of the histone
  • It can correlate either with transcriptional activity or inactivity, depending on which histone tail residue is methylated
  • Mono, di and tri methylation exist
17
Q

Why do histone tail modifications correlate with different chromatin states?

A
  • Histone tail modifications are “read” by other chromatin proteins
  • The interacting chromatin proteins may alter chromatin packaging or bring about other histone modifications
  • They don’t cause altered gene expression but instead mark euchromatin or heterochromatin to be bound by other factors that themselves can alter accessibiility
18
Q

What is the role of histone tails and chromatin proteins?

A
  • Modified histone tails act as docking sites for other chromatin proteins
  • Proteins that bind Me or Ac at specific residues alter chromatin packaging or bring about additional epigenetic charges
19
Q

What are 3 examples of chromodomain proteins?

A
  1. CHD1 - ATP dependent chromatin remodeller
  2. HP1 - essential heterochromatin protein, can recruit DNA methyltransferase 1
  3. CBX2 - part of polycomb repressive complex that lays down H2AK119ub, another epigenetic mark
20
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A
21
Q

What are two examples of long non coding RNAs?

A
  • X inactivation (e.g. Xist)
  • Genomic imprinting (e.g. Kcnq1OT1, Snrpn, Airn)
22
Q

What are some of the possible mechanisms for long non coding RNAs?

A

The common feature is that there is the formation of RNA - protein complexes that influence the regulation of gene expression

23
Q

How do long non coding RNAs guide epigenetic complexes of proteins?

A
  • Sequence complementarity allows the lncRNA to guide the epigenetic modifier complex to a specific location in the DNA
24
Q

What is X Chromosome inactivation?

A
  • X inactivation is an epigenetic dosage compensation mechanism in mammals, so that males and females have the same dose of genes on the X chromosome.
  • Random X inactivation occurs at gastrulation in the embryo, then this epigenetic state is mitotically inherited by each daughter cell
25
Q

How does X inactivation manifest visually in cats?

A
  • There is a ginger colour gene G, and the null allele giving a black coat (g)
  • Additional coat colour genes for white bellies
  • Coat colour patches and X inactivation maintained for the lifetime of the female mammal, due to mitotic heritability of epigenetic marks on the inactive X
26
Q

What epigenetic marks are needed for the inactive X chromosome?

A
  • Xist long non coding RNA bound
  • Low levels of histone acetylation
  • Accumulation of H3K27me and H3K9me
  • DNA methylation of inactivated CpG islands
27
Q

What is Xist?

A
  • Xist is aa 17kb long non-coding RNA that is critical for X inactivation
  • Xist expression from one of the X chromosomes is the first detectable event of X inactivation
  • Xist is expressed from the chromosoem that will become the inactive X
  • Xist RNA coats the inactive X elect in cis
28
Q

How does Xist influence epigenetic silencing?

A
  • Xist RNA binds Hnrnpk, which then recruits polycomb repressive complex 1, which imparts H2AK119ub
  • H2AK119ub recruits polycomb repressive complex 2, which imparts H3K27me
29
Q

In 2015 what extra step of Xist X inactivation method was discovered?

A

Xist binds Spen. Spen may activate Hdac3 to enable deacetylation

30
Q

How heritable is X inactivation?

A

X inactivation status is stable and mitotically heritable. If paternal X was inactivated in the founder cell, all daughter cells will also have the paternal X chromosome inactivated

31
Q

What is Rett Syndrome?

A
  • X-linked neurodevelopmental syndrome caused by mutations in a methyl binding domain protein MeCP2
  • MeCP2 is encoded on the X chromosome
    • Lethal in males before birth (hemizygous)
    • Heterozygous females survive because they are mosaics
32
Q

What happens in there is XCI skewing with Rett Syndrome?

A
  • X inactivation skewing is where is is usually an equal chance of either X chromosome being inactive, but can have uneven split
  • XmutX: if skewing is such that Xmut is silenced 80% of the time it is less severe. If skewed so X is silenced 80% of the time then more severe
33
Q

How could Rett Syndrome possible be treated?

A
  • Try to switch on the inactive X in the brain of Rett patients, meaning wild type copy of MeCP2 was made to bring about normal function.
  • This requires removing many epigenetic marks on the inactive X. the large number of redundant epigenetic marks results in vary stable silencing

MCB 2020 (38 decks)

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