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Brain PD > week 10 part 1 > Flashcards

week 10 part 1 Flashcards

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1
Q

What leads to different brain disorder which are epigenetically affected through different mechanisms?

A
  1. Mutation
  2. Environmental change
  3. Environmental stress
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2
Q

Define Epigenetics

A

A set of molecular mechanism that are involved in the regulation of gene expression

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3
Q

What is gene expression?

A

The umbrella term

A set of mechanism which explain how our genetic code gets read each time in a slightly different way

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4
Q

What is the characteristic of gene expression?

A
  1. Each cells has a different pattern of gene expression
  2. Each anatomical region will have a different pattern of gene expression
  3. Each developmental age will have a different pattern of gene expression
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5
Q

What does epigenetic mechanism play a key role in?

A

Gene expression regulation

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6
Q

What is Conrad Waddington (1942) definition of Epigenetics?

A

The study of heritable traits that do not involve changes in DNA sequence

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7
Q

What is the extended definition of epigenetic?

A

Molecular mechanisms that regulate gene expression without changing DNA sequence

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8
Q

What did Waddington use the term to describe?

A
  1. Refinement of his conception of ‘‘epigenetic landscape’’
  2. Describe the class of external and internal interaction between environment and genes leading to development of phenotype
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9
Q

What was Waddington’s view?

A

There was a landscape of choices facing an organism and the initial constraint and starting point were set by genes

During development, environmental and physiologic forces increasingly came into play

These forces would then operate along with, an in interaction with genes and each other over time and push the organism into typically deeper canals resulting in organisms eventual phenotype

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10
Q

What is the interactive process called and what did it mean?

A
  1. Canalization

2. Individual organisms that may have identical genetic make up could develop radically different phenotypes

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11
Q

What will 2 genetically identical individual have?

A
  1. Slightly different phenotype
  2. Slightly different behaviours
  3. slightly different reactions to heat or to stress
  4. Slightly different features of voice
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12
Q

Plasticity in human brain

A
  1. Essential for brain processes such as learning and memory formation
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13
Q

What does plasticity mediate formation and maintenance of?

A
  1. Synapses
  2. New neurons
  3. Integration of new neurons into existing neuronal network
  4. The reorganisation of neuronal network
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14
Q

What is the brain?

A

Complex multicellular organ which are highly plastic

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15
Q

What is one definition of neuronal tissue?

A

Plasticity

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16
Q

When is plasticity highest specifically during?

A
  1. Prenatal
  2. Early postnatal
  3. Pubertal period
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17
Q

What causes brain disorder?

A

Dysregulation/impairment of plasticity

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18
Q

What does plasticity require?

A

Active changes in gene expression

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19
Q

What does epigenetics mechanism regulate?

A

Gene expression region, cell and context specific manner

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20
Q

What is the most widely studied epigenetic regulation of gene expression?

A

DNA methylation

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21
Q

What is DNA methylation?

A

Addition of chemical group to cytosine which are associated with repression of gene expression

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22
Q

What is histone modification?

A
  1. DNA wraps around the core of histones and these beads are aggregation of protein
  2. Histones have little protruding tail on the end
  3. Susceptible to chemical modification
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23
Q

non-coding RNA

A
  1. RNA that do not become messenger RNA, proteins, peptide

2. non coding RNA to long non coding RNA

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24
Q

DNA methylation

A
  1. Mainly at CpG (5mC)
  2. Responsible for gene silencing
    - inhibition of the binding of transcription factors
    - associated with repressive chromatin-remodelling components
  3. DNA methylation is dynamically regulation
    - CpG can be actively methylated and demethylated by TET proteins in adult neurons
  4. DNAm can also be linked to gene activation
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25
Q

Cycle of Methylation of Cytosine

A
  1. DNMT/DNA
    - methyltransferase - first addition of the methyl groups
    - Maintenance of methylation
  2. TET
    - take methyl group and chemically transform it into intermediates e.g. hydroxymethylation
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26
Q

What are intermediate stages of methylation and where are they found?

A
  1. Very rare

2. Certain brain cells e.g. hippocampus, cortex

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27
Q

What will DNA methylation support?

A

Long term storage information in neurons in cortex

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28
Q

Where is hydroxymethylation found?

A
  1. Brain
    - Hippocampus
    - Cortex
    - Cerebellum
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29
Q

What changes during development in the brain?

A
  1. DNAm

2. Hydroxymethylation

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30
Q

When does DNAm increase?

A

Following learning and maintenance support information storage in cortex

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31
Q

When will levels of methylation change in specific part of the brain?

A

Through aging

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32
Q

What can DNA methylation levels be used to accurately estimate?

A

The age of tissues and cell types forming an accurate epigenetic clock

33
Q

What happens during aging?

A

Global loss of DNA methylation

34
Q

What does histone modifications correlate with?

A

Open or closed state of chromatin

35
Q

What are the main post-translational modification of histone modification?

A
  1. Acetylation
  2. Methylation
  3. Phosphorylation
36
Q

Where does acetylation and phosphorylation (activation) occur in?

A
  1. Serine
  2. Threonine
  3. Tryosine
  4. Lysine
37
Q

What is methylation linked to?

A

Both activation and silencing

38
Q

What does memory formation require?

A

Changes in acetylation and methylation in hippocampus

39
Q

What requires acetylation?

A

Neurons resistance to ischemic or oxidative stress

40
Q

What are found in different neurons?

A

Different HDACs and HATs

e.g. HDAC11 - exclusive to hippocampus and purkinje cells neurons - cognition/memory/motor coordination

41
Q

What are miRNA?

A

20-22 nucleotide long RNAs that act by translational repression or degradation of mRNA targets

42
Q

What does miRNA biogenesis involve?

A

Succession of steps in the cells regulated by RNAses

43
Q

What are examples of RNAses?

A
  1. Drosha and DGCR8 in nucleus

2. Dicer in the cytoplasm

44
Q

What does miRNA associate with?

A
  1. Argonuate proteins in the cytoplasm to form silencing complex (RISC)
45
Q

Where are miRNA abundantly expressed in?

A
  1. Brain

2. Region-specific manner

46
Q

What are miRNA linked to?

A
  1. Neural patterning
  2. Adult neurogenesis
  3. Neuronal activity
  4. Memory formation
47
Q

Why is specific effect difficult to interpret?

A
  1. miRNA biogenesis have pleiotropic functions

2. Dependent on model used, there may be different results

48
Q

What are the main characteristics of Rett Syndrome?

A
  1. Progressive arrest of CNS
  2. Phenotype: problem with language, coordination and repetitive movement. Slower growth and a small head size
  3. RS is a relatively common (1:10,000)
49
Q

What is the main cause of RETT?

A
  1. Loss of function mutation of MECP2 = gene located in X chromosome
  2. Affects exclusively females
  3. Lethal when hemizygous in males
50
Q

What is MECP2 protein abundant as?

A

Histones in neurons and glial

51
Q

What is MECP2?

A

A methyl-binding protein (MBP)
Binds methylated CpGs
Regulate gene transcription in a bidirectional fashion

Also regulates non CpG methylation

52
Q

What does RETT show?

A
  1. Aberrant DNA methylation
  2. Histone PTMs
  3. miRNA levels
53
Q

What is histone forming?

A

Every single piece of DNA/chromatin in our cells

54
Q

What does methyl binding domain interact directly with?

A
  1. CpG sites that are methylated
  2. make physical contact with DNA
  3. When there is mutation - this contact cannot be formed
55
Q

Where is there also mutation in the MECP2?

A

Transcription repression domain

association with other protein

mutation within this part of region - chromatin cannot be active

56
Q

What does MeCP2 interfere with?

A
  1. miRNA maturation machinery

e. g. RNAses Drosha/DGCR8 complex

57
Q

What does MeCP2 influence?

A

DNA methylation profile of many target genes

58
Q

What does MeCP2 bind to?

A

Both methylated and hydroxymethylated cytosine

59
Q

What does MeCP2 associate with?

A
  1. TET
  2. DNMT1 protein
    which mediate global changes in DNA methylation in neurons during development
60
Q

What does MeCP2 help recruit?

A

Transcriptional regulators important for neurogenesis

  1. MECP2+CREB –> BDNF
61
Q

Overexpression of BDNF in MeCP2

A
  1. null mice ameliorates the phenotype in mouse model

2. Reduces neuronal atrophy and improves survival

62
Q

What is CREB . protein?

A

Regulator of neurogenesis

63
Q

What does MeCP2 have?

A
  1. Epigenetic effect

2. Directly responsible for the cognitive and brain developmental impairment seen in RETT syndrome

64
Q

How do we know that depression is a disease that has a strong environmental component?

A
  1. Epidemiological studies

2. Psychological studies

65
Q

What is an example of increased risk of developing depression during lifestyle?

A
  1. Social defeat model in mice
66
Q

What are other forms of social stress?

A
  1. Maternal abandonment

2. Child abuse

67
Q

What does reduced neurogenesis in depression involve?

A

Trophic factors

68
Q

What does stress reduce?

A
  1. BDNF signalling in the hippocampus
  2. Reduced proliferation and plasticity in hippocampus
  3. Reduced hippocampal function
69
Q

BDNF: A neurotrophic factor

A
  1. BDNF
  2. Hippocampus [Neuronal proliferation, survival and plasticity]
  3. Hippocampal function
  4. Mood
70
Q

What is increased in social defeat model?

A

Level of dimethylation of Bdnf promoter

increased condensation - chromatin condensation
Shuts down BDNF gene expression

In parallel global H3 acetylation level are decreased accompanied by increased HDAC5 expression

71
Q

What reduces HDAC level?

A

Chronic antidepressant
Increased H3 acetylation
H3K27 dimethlyation remains unaffected

72
Q

What is sufficient to reinstate BDNF gene expression?

A

Increase in H3 acetylation

73
Q

After social defeat + chronic antidepressant treatment

A
  1. Decreased HDAC5 expression –> + H3 acetylation
  2. Rescue BDNF promoter activity
  3. H3K27 dimethylation unchanged
74
Q

Depressive human brains

A
  1. Increased DNMT expression in brain
  2. Increase/decrease methylation levels of candidate gene including BDNF
  3. loss of BDNF expression
75
Q

Depressed blood + antidepressant

A
  1. Loss of DNMT1 activity
  2. Decreased BDNF methylation
  3. Increased BDNF expression
76
Q

Increased mir-16 expression

A
  1. a miRNA that targets BDNF
  2. In hippocampus
  3. Reduced BDNF transcript
77
Q

Level of mir-1202 reduced

A

Antidepressant treatment reverses this effect

78
Q

Hippocampal autopsy specimen of suicide victims with a history of childhood abuse

A

Alteration of DNA methylation at NR3C1

Alteration of Glucorticoid receptor expression –> HPA axis activation

79
Q

Epigenetic dysregulation in neurodegenerative disorder

A

characterised by intracellular or extracellular deposition of aggregated proteins

Epigenetic mechanism contribute to deposition of these pathological aggregates

Regulate the expression of many proteins involved in amyloid production and/or clearance

Responsible for neuronal death downstream from pathological AB/Tau aggregation

Brain PD (15 decks)

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