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Cell Proliferation and Survival Mechanisms Underlying Disease > Genomic Programming > Flashcards

Genomic Programming Flashcards

1
Q

Define euchromatin DNA

A

Open, active

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2
Q

Define heterochromatin DNA

A

Closed, inactive

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3
Q

What is the role of epigenetic regulation

A

enables us to read genetic information in different manners, enabling us to generate different cells of the body

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4
Q

Layers of the embryonic stem cell (ESC)

A

mesoderm (middle layer)
endoderm (internal layer)
ectoderm (external layer)

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5
Q

What is the Waddington epigenetic landscape

A
  • cell begins at bottom of a single potential well
  • as development proceeds, the single well splits into many more, representing possible differentiation states of the cell
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6
Q

What are nucleosomes

A
  • fundamental subunit of chromatin
  • composed of 8 histones (octomer)
  • H3 and H4 form a trimer
  • H2A and H2B form a histone octomer
  • responsible for DNA compacting and organisation
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7
Q

What type of bonding binds DNA to nucleosome

A

hydrogen bonding -> the negatively charged phosphate backbone of the DNA binds strongly to the positively charged histones and therefore is tightly compacted due to the neutralisation of the negative charge

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8
Q

Role of H1 histone

A

binds linker DNA

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9
Q

How can we obtain individual nucleosomes

A

by treating chromatin with endonuclease micrococcal nuclease (MNase) -> cuts DNA duplex at junction between nucleosomes (linker DNA)

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10
Q

Describe events that take place when chromatin is digested with MNase

A
  • DNA is cleaved into integral multiples of a unit length
  • fractionation of DNA fragments by gel electrophoresis reveals ‘ladder’
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11
Q

Define histone octamer

A

complex of two copies of four histones (H3, H4, H2A, H2B)

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12
Q

Define linker DNA

A

non-nucleosomal DNA present between nucleosomes

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13
Q

Structure of nucleosome

A
  • octomer
  • H32-H42 tetramer (horseshoe shape)
  • H2A H2B pairs fit in as two dimers each binding to opposite face of H3-H4 tetramer
  • protein forms spool with superhelical path which corresponds to binding site for DNA
  • twofold symmetry
  • binds mostly to phosphodiester backbones
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14
Q

Define the globular core

A

histone fold domain of core histones that contribute to the central protein mass of the nucleosome

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15
Q

Role of the N-terminal and C-terminal* tails

A
  • contain sites for covalent modification
  • highly flexible
  • not present in crystal structures

*for H2A and H2B

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16
Q

Covalent modifications of nucleosomes

A
  • transient
  • typically occur at the histone tails (lysines)
  • methylation, acetylation, or phosphorylation (relatively small)
  • can be modified at numerous sites
  • ADP-ribosylation, ubiquitylation, sumoylation (larger)
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17
Q

Effect of lysine acetylation

A
  • occurs on free epsilon amino group of lysine
  • neutralises positive charge residing on NH3 form of the epsilon amino group; reduces electrostatic grip on DNA and exposes transcription factor binding sites
  • makes protein bigger
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18
Q

Effect of methylation

A
  • retains positive charge whether mono-, di- or trimethylated
  • adds hydrophobic interaction
  • recruits proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA
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19
Q

Location and effect of phosphorylation

A
  • occurs on the hydroxyl group of serine and threonine
  • introduces 2 negative charges
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20
Q

How can arginine residues be modified

A
  • can be mono- or dimethylated
  • removing positive charge on Arg weakens interaction with DNA, resulting in opening of chromatin (unstable state)
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21
Q

Name a noncovalent modification of the histone tail

A

proline izomerisation
- regulates lysine methylation and gene expression

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22
Q

Define the histone code

A

the hypothesis that combinations of specific modifications on specific histone residues act cooperatively to define chromatin function

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23
Q

Function of p53

A
  • regulates expression of numerous chromatin-modifying enzymes
  • regulates expression of several key rate-limiting enzymes of the cell metabolism (glycolysis,TCA, folate, methionine)
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24
Q

How does tissue regenerate following injury/damage

A
  • totally or partially
  • stem and progenitors cells around the damage site proliferate and trigger the genome programming process to regenerate damaged tissue
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25
Q

Factors that damage cells/tissues

A
  • injuries
  • malnutrition
  • ischemia
  • infection
  • sun-exposure
  • pH
  • cold/heat
  • pollutants
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26
Q

Excessive cell proliferation

A

cancer

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27
Q

low cell proliferation

A

ageing

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28
Q

Role of damaged cells in tissue regeneration

A
  • induce the repair process and send signals to immune cells to protect from infection and eliminate damaged cells
  • send signals (alarmins) to surrounding stem or progenitor cells to induce proliferation and differentiation
  • all processes must occur simultaneously
29
Q

Importance of epigenetic regulations

A
  • enable stem cells and progenitor cells to re-enter into proliferation and differentiate to regenerate tissue
  • enables them to read genetic information in different manners (plasticity/genome reprogramming)
30
Q

Role of differentiated cells in tissue regeneration

A

can de-differentiate and become stem cells to proliferate and differentiate in the different cell types to regenerate tissue

31
Q

A chromatosome is comprised of…

A

a nucleosome + H1 histone

32
Q

How many times do the eight histone proteins wrap the DNA

A

1.65 times

33
Q

Define solenoid

A

H1 histones aggregate causing 6 nucleosomes to coil together

34
Q

Chromosome territories

A
  • chromatin fibres form chromosome territories in the nucleus of a nondividing cell
  • correlated with gene densities
  • gene rich tend to be located toward the interior of the nucleus
35
Q

How is the DNA/nucleosome interaction regulated

A

post-translational modifications (PTM) e.g. acetylation, methylation, phosphorylation; induced by cell signalling (receptors) and energy metabolism (glycolysis)

36
Q

Function of enzyme Histone Acetyl-Transferase (HAT)

A

transfers Acetyl-CoA produced by glucolysis on lysine to regulate the strength of the binding of the histone to DNA and open chromatin to allow for gene expression

37
Q

What regulates the expression of histone-modifying genes

A

cellular receptors and energy metabolism (glycolysis)

38
Q

Effect of deacetylation of lysine

A
  • regulates interaction with negatively charged phosphate on DNA
  • HAT transfers Acetyl group of Acetyl-CoA to epsilon-amino group of lysines (+) present in N-terminal (tails) of histones. This is a reversible process by HDAC
39
Q

Effect of lysine ubiquitilation

A

increase size of lysine (steric regulation) regulating interactions

40
Q

Arginine (R) and Lysine (K)

A
  • positively charged amino acid
  • can be mono, di, or tri-methylated (Me) which increases size and hydrophobicity, affecting binding of histone to DNA
41
Q

Serine (S) and Threonine (T)

A
  • amino-acids
  • can be phosphorylated (Ph) to repulse histone and DNA
42
Q

Location of histone modifications

A

N-terminal (NH2) and C-terminal domains (COOH)

43
Q

Effect of Arginine deimination/citrunillation

A

neutralises the positive charge of R, weakening the interaction with DNA and thus opening the chromatin

44
Q

Methylation of positively charged AAs

A

regulates hydrophobic interaction with histones, incrementally weakening the interaction between histones and DNA

45
Q

Expression of histone-modifying enzymes

A
  • tissue-dependent manner
  • open/close access to gene
46
Q

Role of promoters

A
  • recruit RNA Polymerase to DNA sequence
  • contain specific DNA sequences such as response elements (TATA box) and transcription factors
47
Q

What is the role of the TATA box

A

provides secure initial binding site for RNA Polymerase

48
Q

What are enhancers

A

DNA sequences localised in non-coding regions and coding regions to increase the likelihood that transcription of a particular gene will occur
- cis-acting (attached to DNA)
- can be located up to 1 Mbp away from gene, upstream or downstream from promoter

49
Q

What are silencers

A

made of DNA and bind TF to inhibit or abolish gene transcription, thus silencing the gene

50
Q

Role of DNMT in DNA modification

A

Governs DNA methylation. 3a and 3b set the patterns, Dnmt1 maintains them

51
Q

Role of demethylase (APOBEC, TETs) in DNA modification

A
  • CG rich region of DNA (CpG islands)
  • maintains DNA methylation homeostasis
52
Q

The enzymatic activity of chromatin-modifying enzymes is dependent on…

A
  • concentration of the metabolite to transfer to targeted histone/DNA
  • concentration of target (histone/DNA)
  • concentration of chromatin modifying enzyme itself
  • allosteric regulator
53
Q

Levels of chromatin-modifying enzyme regulation

A
  1. at gene and protein expression levels
  2. at enzymatic activity level
54
Q

How can chromatin-modifying enzymes be regulated at the gene and protein expression level

A

transcription, splicing, protein translation, protein stability, subcellular localisation

55
Q

How does energy metabolism regulate genome programming

A

modifications catalysed by histone-modifying enzymes and DNA-modifying enzymes are directly dependent on the concentration of their substrates produced by the energy metabolism

56
Q

Metabolite products of the TCA cycle

A
  • Acetyl-CoA
  • ATP
  • SAM
  • NADH
  • FADH
  • ketolutarate
  • UDP-GlcNAc
57
Q

Products synthesised from the folate cycle and methionine cycle

A

amino acids, nucleic acids, S-Adensoyl Methionine (SAM) and glutathione

58
Q

Role of glutathione

A

neutralise oxidative free radicals

59
Q

Why is SAM so important?

A

unique donor of methyl in cells to methylate proteins/histones/DNA/RNA/lipids

60
Q

Role of Acetyl-CoA

A

generates cell building blocks and energy (cellular wood)

61
Q

Lipid biosynthesis results in …

A
  • makes cell signalling molecules
  • makes hormones
  • makes phospholipids to generate cell membranes
  • enables storage of energy as fat
62
Q

Addition of Acetyl-CoA on histones

A

program genome (open/close gene)
(histone acetyl-transferase, HAT -> can be reversed by HDAC to decrease transcription)
Usually coupled with DNA methylation

63
Q

Addition of Acetyl-CoA on transcription factors/splicing factors

A

regulate timing and gene expression level of the different open genes

64
Q

Energy metabolism is responsible for regulating…

A
  • programming of genome and gene expression via production of metabolites used by chromatin-modifying enzymes
  • activities of non-histone proteins (TFs) as metabolites are used by kinases/phosphatases, ubiquitin transferase and also chromatin-modifying enzymes to induce PTMS of non-histone proteins that bind to open genes and induce expression
65
Q

Describe the feedback loop between energy and genome expression

A

gene expression is directly regulated by energy metabolism and conversely energy metabolism is directly regulated by gene expression

66
Q

Input factors altering metabolite homeostasis

A
  • nutrition
  • oxygen
  • heat/cold
  • infections
  • obesity
67
Q

Output factors altering metabolite homeostasis

A
  • physical exercise
  • sun exposure, pollution, tobacco and toxins
  • infection
  • injuries
68
Q

How can sun exposure, pollution, tobacco and toxins alter metabolite homeostasis

A
  • generation of free radicals
  • lipid peroxidation of cellular membranes
  • protein aggregation
  • DNA breaks
  • RNA breaks

Cell Proliferation and Survival Mechanisms Underlying Disease (11 decks)

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