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ANAT0012 > Epigenetics > Flashcards

Epigenetics Flashcards

1
Q

How did Waddington define the term epigenetics in 1942?

A

Changes in phenotype without changes in genotype - to explain aspects of development for which there was little mechanistic understanding

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2
Q

What do we now know 3/4 of a century later?

A

Epigenetic mechanisms transduce the inheritance of gene expression patterns by adapting chromatin, the physiological form of our genome

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3
Q

What do epigenetic modifications facilitate?

A

Our adaptation to ever-changing conditions in an age- and generation-specific manner

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4
Q

What is DNA wrapped around?

A

Positively charged proteins called histones, covered in chemical tags (epigenome)

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5
Q

What does tight wrapping do?

A

Makes inactive genes unreadable by preventing access by transcriptional machinery

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6
Q

How is the access differentially regulated?

A

HATs and HDACs which add or remove an acetyl group, respectively

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7
Q

What does the addition of a negatively charged acetyl group to lysine residues lead to?

A

Removes the positive charge from histone N-termini, reducing their interaction with the negatively charged DNA phosphate backbone - opens DNA allowing transcriptional machinery to bind

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8
Q

How is repression achieved?

A

Reverse mechanism - removal of an acetyl group increases the interaction and allows histones to tightly interact with DNA - prevent transcriptional machinery from binding, silencing gene expression

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9
Q

Histone methylation

A

On arginine residues (PRMT) and lysine residues (HMT with SET domain) leading to either activation or repression e.g. H3K4me3 (active) and H3K4me2 (inactive) // can also be methylated on arginine or lysine residues, and depending on the methylation pattern can lead to either repression or activation of transcription

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10
Q

Where does DNA methylation occur?

A

5’ carbon on cytosine residues, mediated by DNA methyltransferases. Usually on CpG islands (>200bp, C/G > 50%)

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11
Q

What do promoters contain?

A

Majority have CpG islands - high levels of DNA methylation at these regions leads to silencing (Fry et al., 2011)

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12
Q

Why does methylation silence genes?

A

Inability of transcription factors to bind or enhanced binding of MBDs

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13
Q

What do MBDs do?

A

Recruit additional proteins, such as HDACs and other chromatin remodelling proteins, forming heterochromatin

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14
Q

Methylation patterns in monozygotic twins?

A

Same at young ages, different at later ages due to different environmental cues (Fraga et al., 2005)

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15
Q

What are miRNAs?

A

Most significant epigenetic regulators discovered in last decade, very short (18 - 25 bp long) and instead of coding for proteins, regulate gene expression by degrading target mRNAs and/or inhibiting their translation (Prosser et al., 2011)

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16
Q

What are the characteristics of ASDs?

A

Problems with social communication and interaction, restricted/repetitive behaviours, attention deficits, sensory and motor abnormalities, cognitive impairments and epilepsy

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17
Q

What major gene network is associated with ASDs?

A

Neurodevelopment and cell signalling, half of those genes are related to epigenetic mechanisms

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18
Q

What have blood and brain samples indicated?

A

Epigenetic modifactions underlie the pathology of ASDs

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19
Q

How many key genes are associated with ASDs, and in what context?

A

5 key genes (OXTR, GAD1, MECP2, EN2, RELN) in regards to their epigenetic mechanisms, identified by methylation analysis (Loke et al., 2015)

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20
Q

What is the OXTR involved in?

A

Social memory, recognition and anxiety

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21
Q

What was found in the OXTR promoter in ASD patients?

A

23-39% increase in DNA methylation, associated with reduced expression in the temporal cortex - social cognitive impairments of ASDs

22
Q

What was found in the GAD1 promoter?

A

3% increase in hydroxymethylation in ASD cerebella, suggesting suppressed GAD1 activity is related to the pathogenesis of ASDs

23
Q

What was found in the Engrailed-2 promoter?

A

Involved in pattern formation in neural development, 10-20% increase in DNA methylation and reduced RNA and protein levels in ASD cerebella

24
Q

What is reelin involved in?

A

Secreted extracellular matrix glycoprotein, involved in neuronal migration and positioning in the developing brain and modulation of synaptic plasticity in adult - increased hydroxymethylation at promoter in ASD cerebella

25
Q

How is MeCP2 related to ASDs?

A

While this is a gene mutation, encodes an epigenetic regulatory molecule whose dysregulation can lead to Rett syndrome

26
Q

Where has altered DNA methylation been seen in psychosis?

A

BDNF, reelin, 5HT1A, 5HT2A, SERT (Abdolmaleky et al., 2015)

27
Q

Example of abnormal histone modification in SCZ?

A

Decreased acetylation at the GAD1 promoter (H3K9K14)

28
Q

What do most of the data point towards?

A

The importance of dysregulated histone modifications, such as the dysregulation of HDAC3 in the temporal cortex and increased expression of HDAC1 in the frontal cortex of SCZ patients

29
Q

What has been at the forefront of experimental remedies for psychosis?

A

Therapeutic agents that modulate histone codes e.g. valproate, a non-specific HDAC inhibitor used to increase H3 acetylation in SCZ patients

30
Q

What have dysregulated miRNAs also been implicated in?

A

Psychotic disease - abnormal expression reflects the pathological state of the organism

31
Q

What is a promising non-invasive and accurate biomarker for disease?

A

miR-181b (Abdolmaleky et al., 2015)

32
Q

What does the 22q11.2 microdeletion do?

A

Introduces de novo cases of SCZ in the population

33
Q

What does the 1.5Mb region encode?

A

Contains the gene Dgcr8 which is necessary for miRNA biogenesis

34
Q

What resulted from the microdeletion 22q11.2?

A

Downregulation (by 20-70%) of 10-20% of miRNAs, including a number of clusters involved in neural development (Stark et al., 2008)

35
Q

What is Rett syndrome?

A

Progressive neurodevelopmental disorder starting in early infancy and most common cause of mental retardation in females (1:10000)

36
Q

How does Rett syndrome arise?

A

Mutation in methyl-CpG-binding protein 2 located on the X chromosome, therefore showing high lethality in males (miscarriage or still birth)

37
Q

Rett syndrom in females?

A

As females have 2 X chromosomes, one is randomly inactivated (due to high levels of DNA methylation and reduced levels of histone acetylation) leading to a mosaic organism where only some cells express the functional version of MeCP2

38
Q

Where does MeCP2 bind and what does it do?

A

On the DNA sequence, recruits additional proteins. Aside from transcriptional repression, involved in chromatin compaction and loop formation as well as transcriptional activation (together with CREB and an activator)

39
Q

How many mutations have been identified?

A

Over 600 (Liyanage and Rastegar, 2014), most likely leading to partial or complete loss of function and thus inappropriate gene expression

40
Q

What did Bird provide proof-of-principle for in 2007?

A

Murine Rett syndrom can be reversed by reintroducing a functional version of the MeCP2 gene, suggesting that neurons do not die and neural defects are not permanent

41
Q

How did Guy et al (2007) extend this model?

A

Inserted a loxStop casette to silence MECP2. When reactivated by deletion of the Stop casette, neuronal function was restored confirming that the molecular preconditions for normal MeCP2 activity are preserved in its absence

42
Q

What is highly conserved in MECP2?

A

DNA-binding domain and corepressor-binding domains which are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility (Tillotson et al., 2017)

43
Q

How do past experiences influence behaviour in adulthood?

A

Nutritional factors (methionine, folate and vitamin B12 key players in methylation reactions), maternal distress, drug abuse and maternal smoking

44
Q

What does stress during pregnancy lead to?

A

Increased methylation at the BDNF exon IV and decreased methylation at the corticotropin releasing hormone promoter leads to increased HPA axis responsiveness and anxiety-like behaviour in mice

45
Q

How does response to stress during adulthood correlate with maternal grooming?

A

Whether a pup grows up to be anxious or relaxed depends on the mother that raised it, not the birth mother (Weaver et al., 2004)

46
Q

What other epigenetic modifications can influence behaviour in adulthood?

A

Insufficient maternal care, type of milk fed and childhood trauma

47
Q

What did McGowan et al (2009) show?

A

Higher DNA methylation at promoter for glucorticoid receptor gene in brains of suicide victims that had experienced childhood trauma compared to controls

48
Q

What does an SNP in the gene coding for FKBP5 do?

A

FKBP5 regulates the stress response by binding of stress hormones to the GR, interacts with childhood trauma to predict an increased risk of PTSD and suicide (Roy et al., 2010)

49
Q

What happens in response to early-life stress?

A

Glucocorticoid response element upstream of the gene is demethylated, leading to increased expression of FKBP5 and hypersensitivity to stress (Klengel et al., 2013)

50
Q

What happens in response to adult-life stress?

A

Demethylation is not seen, despite increased levels of glucocorticoids, highlighting the drastic effect past experiences can have on behaviour in adulthood

ANAT0012 (3 decks)

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