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Functional Ageing > Epigenetics and Ageing > Flashcards

Epigenetics and Ageing Flashcards

1
Q

What is the central dogma of genetics?

A

DNA is transcribed to RNA and then translated to protein

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2
Q

What is the first level of control over the process of cells expressing proteins?

A

epigenetics

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3
Q

What is epigenetics?

A

the interactions of genes with their environment which bring the phenotype into being

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4
Q

What are environmental influences on the epigenome?

A
  • psychological state
  • social interactions
  • alternative medicine
  • therapeutic drugs
  • drug abuse
  • disease exposure
  • exercise
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5
Q

What type of process is epigenetic modulation?

A

reversible

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6
Q

What does reprogramming do?

A

erase most epigenetic tags so that the fertilised egg can develop into any type of cell

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7
Q

What do reproductive cells have?

A

specialised function with lots of epigenetic tags

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8
Q

What are the 4 major mechanisms of epigenetics?

A
  • DNA methylation
  • covalent histone modifications
  • chromatin remodelling
  • non-coding RNA
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9
Q

What is DNA methylation?

A

covalent addition of a methyl group at position 5 of cytosine to form 5-methyl C

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10
Q

Where does DNA methylation occur in humans?

A

at cytosines next to guanines linked by phosphate CpG sites

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11
Q

What are CpG islands and what do they do?

A

clusters of CpG groups that regulate gene expression in the gene body, promoter region or UTR

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12
Q

What do methyl-binding domain proteins do?

A

recruit histone deacetylases (HDACs) and co-repressors by DNA methyltransferases (Dnmts) to form transcription repressor complexes

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13
Q

What do transcription repressor complexes do?

A

prevent TFs from binding with their specific DNA sequences causing silence or inhibition of gene expression

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14
Q

What do ten-eleven translocases do?

A

collaborate with DNA damage 45-beta, Dnmts and HDACs to catalyse oxidation of 5mC to 5-hydroxymethylcytosine i.e. promote demethylation

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15
Q

What is a chromosome made up of?

A

DNA wrapped around histones which then form octets to produce nucleosomes

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16
Q

What is covalent histone modification?

A

reversible and dynamic that involves both enzymes and signals to produce modified histones with diverse biological functions

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17
Q

What is histone modification dependent on?

A

the histone, site and amino acid involved

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18
Q

What are the 5 histone modification types?

A
  • acetylation
  • methylation
  • ubiquitination
  • sumoylation
  • phosphorylation
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19
Q

What are the 3 class of enzymes involved in histone modifications?

A
  • writers that add groups
  • erasers that remove groups
  • readers that identify the modification and alter gene activity and protein production
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20
Q

What is chromatin?

A

a mixture of DNA and proteins that forms the chromosomes; the condensed form of DNA

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21
Q

What is chromatin remodelling?

A

the rearrangement of chromatin from a condensed state to a transcriptionally accessible state, allowing TFs or other DNA binding proteins to access DNA and control gene expression

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22
Q

What is heterochromatin?

A

a highly condensed form of DNA and mostly consists of repetitive DNA sequences and non-coding RNA transcripts

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23
Q

What is euchromatin?

A

the opposite of heterochromatin made up of repeating nucleosomes

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24
Q

What are the 4 major families of ATP-dependent chromatin remodelling factors?

A
  • SWI/SNF
  • ISWI
  • INO80/SWR1
  • NuRD
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25
Q

What are the 3 main chromatin remodelling mechanisms?

A
  • sliding over
  • histone eviction
  • replacement with variant histones
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26
Q

What happens in sliding over?

A

conserved ATPase motor slides nucleosomes along DNA through 2 mechanisms: twist diffusion and loop/bulge propagation

27
Q

Wha percentage of the human genome does not code for any protein?

A

97%

28
Q

Give examples of non coding RNA

A
  • shRNA
  • miRNA
29
Q

How does non coding RNA alter gene expression?

A

without altering the genetic code at the post-transcriptional stage by degradation of mRNA

30
Q

Where does lincRNA play an important role?

A

developmental processes such as X-chromosome inactivation and genomic imprinting

31
Q

What does hypomethylation do?

A

silence local genes

32
Q

How does DNA methylation affect ageing?

A
  • ↓ global methylation
  • ↑ local methylation
33
Q

What do altered histones do during ageing?

A

reduce the expression of essential genes

34
Q

What are transposons?

A

nucleic acid sequences in DNA that can “jump” to different locations within a genome and can sometimes create or reverse mutations and alter the cell’s genetic identity and genome size

35
Q

What does transposition often result in?

A

duplication of the same genetic material

36
Q

What happens if the histone is lost?

A

the DNA is loose and can be constantly transcribed which results in the translation of many unwanted proteins and a histone modification imbalance

37
Q

How can methylation be detected?

A

direct PCR product sequencing or sub-cloning sequencing

38
Q

What happens when telomeres shorten?

A

many genes are lost, and cells become dysfunctional

39
Q

What is the hazard ratio?

A

the relative risk of the event (e.g. disease progression) happening in one arm of a trial compared to another over the time of the trial arm difference between groups that has a real impact on biology

40
Q

What does a HR of 1, 2 and 0.5 mean respectively?

A
  • 1 = no difference
  • 2 = double the risk
  • 0.5 = half the risk
41
Q

What is chronological age?

A

a person’s age from the day they were born until the present

42
Q

What is biological age and what is it determined by?

A

the age of the entire organism (cells) determined by telomere length, metabolite function, the epigenetic clock or environmental factors (lifestyle)

43
Q

What is premature ageing?

A

when the biological age is above the chronological age

44
Q

What is age acceleration at adulthood and new born babies respectively?

A
  • adulthood = 40%
  • newborns = 100%
45
Q

What is age acceleration?

A

the rate at which an individual is growing that slows down with age

46
Q

What is the epigenetic clock?

A

a biological clock to measure the age of most human tissues, cell types, and organs in the same individual which can help in predicting the ageing process

47
Q

How many CpG sites were identified by Hannum and Horvath respectively?

A
  • Hannum = 71
  • Horvath = 353
48
Q

Give examples of age-related conditions linked to epigenetic age acceleration in specific tissues

A
  • AD in prefrontal cortex
  • cancer in the blood
  • Down syndrome in the blood and brain
49
Q

What is DNAm phenoage?

A

a phenotypic age

50
Q

What does the heterochromatin loss model of ageing suggest?

A

the loss of heterochromatin that accompanies aging leads to changes in global nuclear architecture and the expression of genes residing in those regions, directly or indirectly causing aging and cellular
senescence

51
Q

What is senescence?

A

when cells stop dividing and avoid death by releasing SASPs (senescence associated secretory proteins) which affects and spoils neighbouring cells

52
Q

What is epimutation?

A

when an abnormal chromatin state leads to reduced gene expression and an unstable genome

53
Q

What is a cause of ageing in yeast?

A

a global loss of core histone proteins from the genome

54
Q

What was observed during yeast replicative ageing?

A

all genomic regions showed transcriptional up-regulation, presumably because of increased access of the transcription machinery to the DNA sequences

55
Q

How does calorie restriction work?

A

autophagy; the process by which old and damaged cell parts are reused

56
Q

What are the most prominent histone modifications known to affect the longevity process?

A

acetylation and methylation of lysine residues

57
Q

What are crucial for regulating chromatin dynamics?

A

non-allelic variants of most histone proteins that are different in their primary sequence

58
Q

Why is it easy to modify the epigenome?

A

epigenetic alterations are reversible

59
Q

What is SIRT1?

A

an NAD+ dependent histone deacetylase that catalyses the removal of acetyl groups from a number of non-histone targets

60
Q

What are the downstream effects of target deacetylation?

A

changes in cellular metabolism as well as cell survival and senescence effects

61
Q

What are the metabolic effects of increased SIRT1 dosage?

A
  • ↓ glucose
  • ↓ insulin
  • ↑ glucose intolerance
  • ↑ insulin sensitivity
  • ↑ mitochondrial function
  • ↑ fatty acid oxidation
  • ↑ healthspan
62
Q

How does calorie restriction increase lifespan?

A

through SIRT1 activation

63
Q

What environmental inputs increase healthspan and lifespan?

A
  • diet restriction
  • regular circadian cycle
  • exercise
  • pheromones
  • systemic factors

Functional Ageing (4 decks)

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