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Translational Medical Sciences > Epigenetics in health and disease > Flashcards

Epigenetics in health and disease Flashcards

1
Q

What is epigenetics

A

reversible regulation of gene expression by alteration to DNA methylation and chromatin structure occurring independent of the DNA structure

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2
Q

What is the difference between gene expression by DNA and epigenetics

A
  • DNA sequence mediates what specific mRNA molecules are synthesised
  • Epigenetic modifications mediate how much of a specific mRNA is made and when are where it’s synthesised
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3
Q

Why are epigenetics important

A
  • imp for cell differentiation
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4
Q

Name some types of epigenetic modifications

A
  • DNA methylation
  • Nucleosome positioning
  • histone modification
  • DNAse hypersensitive site
  • 3D chromatin architecture
  • smRNA and lncRNA (non-coding)
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5
Q

What does DNA methylation consist of

A
  • addition of methyl group to C5 position of cytosine
  • most methylation occurs in sequence context 5’-CG-3’
  • occurs almost exclusively at cytosines followed immediately by guanine CpG dinucleotide
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6
Q

What is CpG

A
  • Cytosine-guanine dinucleotides
  • primary targets for DNA methylation
  • interspersed throughout DNA
  • A hotspot for CpGs is called a CpG island
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7
Q

How does DNA methylation affect gene expression

A
  • ~50% of human genes have a CpG island in the promoter region
  • methylation of CpG in promoter region is related to transcriptional silencing
  • methylation inhibits transcription binding either directly or via altered histone acetylation
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8
Q

What is the mechanism of action of DNA methylation

A
  • DNMTs add methyl groups derived from SAM to the CpG islands to methylate them
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9
Q

Name the different types of mammalian DNMTs

A

1, 2, 3a, 3b, 3L

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10
Q

What roles do the different types of DNMTs play

A
  • DNMT1: maintains methylation during DNA replication, requires hemi-methylated DNA substrate and reproduces pattern of DNA methylation on newly synthesised DNA strand
  • DNMT3a and 3b: de novo methylases, add methyl group to previous unmethylated CgP nucleotides, re-establish methylation pattern
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11
Q

Name a factor of DNA methylation and what role does it play

A
  • 5hmC
  • found abundantly in embryonic cells and in the brain
  • positively correlated to gene expression
  • plays a role in active demthylation to promote gene expression
  • conversion of 5mC to 5hmc by TET blocks repressive proteins that typically would’ve been recruited to 5mC
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12
Q

What is passive demethylation

A
  • demtheylation occurring during cell differentiation and mammalian development
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13
Q

What roles does DNA methylation play

A
  • long-term silencing of genes
  • silencing of repetitive elements (like transposons)
  • inactivation of X chromosome
  • expression and establishment of imprinted genes
  • suppression of viral genes and other deleterious elements which are a part of the host genome
  • carcinogenesis
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14
Q

Summarise the functioning of DNA methylation

A
  • displaces transcription factors

- attracts methyl binding proteins

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15
Q

How does DNA methylation inhibit transcription?

A
  • alters the shape of the response element that the transcription factor binds to
  • Methyl-binding proteins recruit different co-repressor complexes
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16
Q

What is chromatin

A
  • In a non-dividing cell, nucleus is filled with thin packing material called chromatin
  • chromatin provides scaffolding for the entire packaging of our genome
  • chromatin is made up of DNA, proteins (mainly histones and some non-histone proteins) and RNA
  • Chromatin also regulates accessibility to DNA by modifications in chromatin structure
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17
Q

What forms is chromatin found in

A
  • Heterochromatin: compact, generally not active

- Euchromatin: less compact generally active

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18
Q

What is a histone

A
  • part of chromatin
  • assembles into octameric complexes
  • highly conserved
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19
Q

What is a nucleosome

A

DNA wraps around histones to form nucleosomes

- nucleosomes are the building blocks of chromatin

20
Q

What is a nucleosome made up of

A

2 copies each of 4 histones(H2A, H2B, H3, H4)

21
Q

What is the function of the nucleosome

A
  • as a signalling hub by providing a scaffold for the binding of chromatin enzymes
  • displays PTMs which:
    • regulate recruitment of chromatin enzymes
    • tunes both nucleosome stability and higher order compaction of chromatin
22
Q

Describe possible histone modifications

A
  • Acetylation (HAT/HDAC): reduces affinity for adjacent nucleosomes and relaxes overall high order chromatin structure, increasing access to DNA
  • Methylation (DNMTs): recruit silencing or regulatory proteins that bind methylated histones
23
Q

Give an example of how gene silencing works

A
  • H3K27ac is an enhancer marker that can be used to distinguish between active and poised enhancer elements
  • H3K4 = activation, whether it’s methylated or acetylated
  • H3K9ac =activation
  • When H3K27 is trimethylated, it is tightly associated with inactive gene promoters
  • H3K9me =silenced
24
Q

What is uniparental disomy

A
  • when both copies of chromosomes come from one parent
  • have loss of expression of some genes and increased expression of others
  • causes diseases due to changes in epigenotype and disruption of genomic imprinting
25
Q

What is genomic imprinting

A
  • one copy of a gene is silenced due to its parental origin
  • some genes are normally
    active only when they are inherited from a person’s father; others are active only
    when inherited from a person’s mother
  • Imprinting is achieved by DNA methylation
  • Prader-Willi Syndrome – cognitive and sexual deficiencies as well as obesity and excessive hunger
  • Angelman Syndrome: sleep, mental and developmental deficiencies and uncontrollable laughter
26
Q

Give a real life example of genomic imprinting

A
  • Ligers and tiglons

- changes in appearance and size depending on different imprinted genes from mother or father

27
Q

What environmental factors can affect the epigenome

A
  • epigenome is particularly susceptible to deregulation during embryogenesis and the perinatal period
28
Q

Why is the epigenome sensitive during the perinatal period and embryogenesis

A
  • DNA synthesis rate is high
  • Time when elaborate DNA methylation patterns and chromatin structure required for normal tissue development are established
29
Q

Give an example of how epigenetics has been observed in animal models

A
  • Difference caused by DNA methylation at the agouti viable yellow (Avy) gene
  • yellow mouse has High risk cancer, diabetes, obesity
    Reduced lifespan
  • with maternal supplements like zinc and choline the agouti mouse is brown in colour and has Lower risk of cancer, diabetes, obesity and a Prolonged life
30
Q

Name some factors that can affect the epigenome of a baby during neonatal periods

A
  • diet
  • toxins/pollutants
  • drugs/alcohol
  • radiation
  • psychosocial factors
  • climate
  • hormones
  • medication
31
Q

What is Lamarckism

A

the idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring (also known as heritability of acquired characteristics or soft inheritance)

32
Q

How can a gene reset its epigenome

A
  • erase epigenetic marks of somatic cells
  • establish those of germ cells
  • on fertilisation, erase marks of germ cells and
  • establish those of totipotency / development
33
Q

How are transgenerational effects inherited

A

Transgenerational effects are inherited via paternal gametes.

34
Q

What genes are frequently mutated in cancer

A
  • genes that regulate epigenomic regulatory factors
35
Q

Name two recognised genes mutated in hematopoietic malignancies

A
  • DNMT3a and TET2
36
Q

What is the role of DNA methylation in cancer

A
  • Hypermethylation (Promoter silencing of tumour suppressing genes)
  • Hypomethylation (genetic instability, activation of proto-oncogenes)
  • Deamination (mutation)
37
Q

Name a tumour suppressor gene that has been implicated in cancer

A
  • MLH1: mismatch gene, frequently mutated in colon cancer
  • Micro-satellite instability phenotype (characterised by multiple genetic alterations)
  • 10-15% of non-familial colon cancer have a similar phenotype
  • Majority of these cancers harbour epigenetic silencing of a non-mutated MLH1 gene
38
Q

Name some mutations linked with acute myeloid leukemia

A

DNMT3A

TET2

39
Q

What is the hypothesis about methylator phenotype

A
  • DNA methylation is an alternative model of tumorigenesis
  • DNA hypermethylation silences tumour suppressor genes, which causes the accruement of mutations that inevitably lead to cancer
  • CGP island methylator (CIMP) phenotype has been associated with several types of cancers
40
Q

How can you screen for novel genes epigenetically silenced in cancer

A
  • Identify novel cancer-related differentially methylated genes
  • Validated using standard techniques such as QMSP; Pyrosequencing
41
Q

What is the role of DNA methylation of tumour progression

A
  • aids invasion of carcinogenic cells
42
Q

Why is DNA methylation a good potential biomarker

A
  • DNA methylation changes are a common event in carcinogenesis
  • easy to detect and with a high degree of sensitivity
  • DNA methylation is more stable than RNA or Protein based markers
43
Q

Give some examples of DNA methylation cancer screening marker

A
  • Prostate cancer (GSTP1)
  • Lung cancer (SHOX2)
  • Colorectal cancer (Sept9)
44
Q

What aspect of epigenetics is being tested as a possible biomarker

A
  • circDNA

- molecular alterations found in tumour cells is reflected in circDNA released from tumour into the blood

45
Q

Describe a technique that’s used to interrogate the epigenome

A
  • Bisulphite conversion
  • Use sodium bisulfite to differentially convert unmethylated cytosine residues to
    uracil + methylated cytosines are unmodified
  • Identify methylated cytosine via various downstream nucleic acid analysis e.g. PCR,
    qPCR and sequencing
  • Can identify individual methylation sites and quantify the level of methylation
46
Q

Name some target-specific epigenomic lab techniques and some genome wise ones

A 
Targeted
- Direct sequencing
- Cloned Bisulfite PCR
- Bisulfite-pyrosequencin
NGS
- MethylC-seq
- RRBS
- Target Capture
- Affinity Based
- MeDIP
- MIRA

Translational Medical Sciences (8 decks)

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