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1

What are epigenetic mechanisms?

- Create molecular environment that shape accessibility of genes to transcription machinery
- Regulate levels of gene transcription and sensitivity to change by extrinsic DNA binding transcription factors
- Epigenetics do not change the underlying DNA sequence

2

What do epigenetic mechanisms regulate?

Epigenetic mechanisms regulate growth, development, and maintenance of physiological homeostasis across the life course
- Development and tissue homeostasis
- Adaptive and maladaptive responses to environmental factors

3

What molecules are involved in epigenetic mechanisms?

- DNA methylation of CpG dinucleotides
- Covalent Modifications of nucleosomal histones within chromatin
- Non-histone proteins that generate, recognise or remove DNA methylation, histone modifications
- Non-coding regulatory RNAs

4

Give an example of the epigenetic mechanism that directly acts on promotors or enhancers

- Steroid hormones e.g, ecdysone (potent regulators of gene transcription) bind to its TF receptor (ecdysone receptor) which undergoes a conformational change that allows entry to nucleus. It can then bind to recognised DNA and recruit proteins which stabilise the interaction between the RNA polymerase and the promotor regions of the ecdyson receptor

5

How does metylation of CpG dinucleotides result in gene regulation?

- Methyl group added to cytosine bases using DNA methyltransferases.
- Changes the interior surface of the major groove of DNA which changes the ability for TF's to recognise the DNA surface
- It produces recruitment sites for DNA binding proteins to mask the major groove stopping direct contact to DNA. This blocks the ability of DNA to be recognised, read and decoded

6

How does the DNA sequence of promotor regions allow the regulation of gene expression?

Promotor sequences in genes are rich in these nucleotides. Whether a gene is active is often determined by the methylation state of these CpG nucleotides

7

How can the methylation of core histones regulate gene transcription?

In transcriptionally silent chromosomes, there are histones that are highly methylated. The combination of methylated histones and methylated cytosine residues shuts the locus down

8

How can the acetylation of core histones regulate gene transcription?

Transcriptionally active chromatin has a much more open structure (nucleosome free regions of DNA) and the nucleosomes are instead hyper acetylated. These negatively charged acetyl groups help the DNA to remain accessible to TFs by maintaining the chromatin in an uncondensed state

9

What part of the core histones are modified?

The N terminal tails of core histones are targets of a wide range of different histone modifications by enzymes that function as modification “writers”.

10

What is the role of histone Acetyltransferases?

Histone Acetyltransferases add acetyl groups to multiple lysines in the N-terminal tails of core histones

11

What is the role of Histone Methyltransferases?

Histone Methyltransferases add methyl groups to specific lysines or arginines in the N-terminal tails of core histones

12

What is the role of Histone kinases?

Histone kinases add phosphoryl groups to Serines / Threonines of core histones

13

How are histone modifications recognised?

Recognised by proteins with modification-specific binding domains – modification “readers”

14

What are acetylated histones recognised by?

Proteins with bromodomains

15

What are methylated histones recognised by?

Proteins with chromodomains

16

What are modification erasers?

If there are no proteins bound then these modifications can then be selectively removed
- For acetylation, the protein to remove it is histone deacetylases and for methylation, the enzyme is histone demethylases

17

How can long non coding RNAs regulate gene expression?

- Can be several KB in length and full of complex tertiary structures e.g. hair pin loops. These loops can interact with chromatin regulatory proteins.
- These RNA protein complexes can impact on the structure and function of the chromatin of which they are apart

18

Give an example of a long non coding RNA that regulates gene expression

For example, the X chromosome inactivation RNA called Xist. Has complicated hair pinned loops which allow interaction with proteins which allow selective shutting down of one of the two X chromosome’s in female cells

19

Give examples of short non coding RNAs

MicroRNA
PiRNA

20

How can Micro RNAs regulate gene expression?

Micro RNAs are present in the cytoplasm and interfere with the transaction of existing mRNA that is complementary to the micro RNA
- Can also lead to the destruction of the mRNA once hybridisation occurs

21

Where are piRNA found?

Nucleus

22

What is the role of piRNAs?

piRNAs have complementarity with nascent mRNAs. These RNAs encode transposable elements which controls the expression of transposable elements in the genome.

23

How do piRNAs control gene expression of transposable elements?

- They suppress the expression of transposable elements RNA through by recruitment of PIWI proteins to transposon loci and promote formation of transcriptionally silent heterochromatin
- They also act as nucleation signals for chromosome modification enzymes which shut the transposable mechanism down
- piRNA that are exported from the nucleus can also act in the cytoplasm to promote inhibition or degradation of transposable mRNA

24

What is meant by epigenetics ensuring a robust phenotype?

Epigenetic mechanisms guide development and ensure robust, stable phenotypes are produced through reliable mechanisms that regulate expression of the genome according to a predictable schedule.

25

What is meant by epigenetics ensuring plasticity?

Epigenetic mechanisms are also flexible and sensitive to physiological signals, which may originate within an organism or as a consequence of changes in the external environment

26

What kind of changes can the phenotypic plasticity of epigenetic mechanisms lead to?

This can either be beneficial changes or create capacities for the emergence of maladaptive chronic disease states

27

What are the two types of phenotypic plasticity?

Reaction norms
Polyphenisms

28

What are reaction norms in relation to phenotypic plasticity?

Reaction norms are ranges of phenotypic characteristics that are continuous and proportional to the environmental stimulus

29

Give an example of reaction norms in relation to phenotypic plasticity

Phenotypic Plasticity engenders beneficial adaptations that can improve fitness. Used resistance training to develop muscle hypertrophy. This is driven by PGC1alpha TF. The more resistance training, the more PGC1alpha, the more muscle hypertrophy

30

What did Ruas et al, 2012 discover about PGC1-alpha?

- PGC1-alpha has two regulatory elements with one being responsive to resistance training which leads to a form of PGC1 alpha that leads to hypertrophy.
- If over express this form of PGC1 alpha in mice then muscle size increases.
- If do different training e.g. running then there is a different form of PGC1alpha activated and increases the metabolic function of the muscle and allow it to function over long periods of time
- Saw that gene expression changes with muscle loading and unloading and saw the change in DNA methylation of the regulatory agents around these genes