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BIOL3017 - Molecular and structural basis for disease > Epigenetics > Flashcards

Epigenetics Flashcards

1
Q

What % of pregnancies does FGR (fetal growth restriction) occur in?

A

5%

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2
Q

What is FGR

A

Fetal growth restriction

A baby’s growth slows or stops in utero

Affects trajectory throughout pregnancy and throughout baby’s life

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3
Q

Causes of FGR

A

Chromosomal defects

Placental insufficiency – supply of nutrients from mother

Environment ~ multiple gestation (twins, triplets), smoking, alcohol, or abusing drugs, maternal illness or infections nutrition or stress

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4
Q

Explain how the placenta can be studied at lots of different levels

A

Size and structure

Transport capacity - Nutrients, toxins, IgG

Blood flow - Maternal, fetal

Metabolism - Nutrients, drugs

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5
Q

Whats one thing the placenta is important for

A

Amino acid transfer from mother to fetus, to allow proteins to be made

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6
Q

Explain risks of death or illness in FGR

A

Babies can be stillborn

At risk of developing lifelong disabilities (e.g. cerebral palsy)

At risk of developing non-communicable diseases in adulthood

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7
Q

What non- communicable diseases do small babies have a higher risk of?

A

Hypertension

Raised serum cholesterol

Impaired glucose tolerance

Type 2 diabetes

Obesity

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8
Q

Define gene

A

nucleotide sequence required to direct protein synthesis

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9
Q

Stages of blastocyst development

A

Oocyte
Zygote
2-cell
4-cell
8-cell
Morula
blastocyst (stage where differentiation is occurring - therefore different genes and proteins beginning to be expressed)

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10
Q

Explain gene expression in a developing embryo

A

Translation into protein is continued throughout the preimplantation period

Messages (mRNAs) inherited from the oocyte (maternally inherited) regulate embryo development early on

During early cleavage, the embryonic genome is gradually switched on to initiate de novo transcription.

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11
Q

What is epigenetics?

A

The study of heritable changes in gene activity that occur without a change in the DNA sequence

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12
Q

Explain how transcription factors control gene expression

A

TFs bind to promotor/control region (GRE = gene regulatory element)

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13
Q

Define epigenome

A

The Genome-Wide Epigenetic State, All of the Epigenetic modifications within the Cell’s Genome

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14
Q

What are epigenetic tags

A

Epigenetic marks or modifications

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15
Q

What are epigenetic modifiers

A

Enzymes that catalyse the addition or removal of epigenetic tags

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16
Q

What are the epigenetic mechanisms

A
  1. Chemical modifications of DNA e.g. methylation
  2. Post Translation Modifications of Histone Tails
  3. Histone Variants
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17
Q

What does CpG mean?

A

cytosine next to a guanine

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18
Q

Explain CpG methylation

A

Cytosine (CpG) is methylated to 5-methyl cytosine (5mC)

sits within groove id DNA, and provides a physical bloc that stops TFs from binding to DNA groove (Can also be a mark for methyl binding proteins)

Group attcached to DNA by DNA methyltransferase - DNMT

  • Most common
  • Stable
  • No effect on base pairing
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19
Q

Which DNMTs are used in De-novo methylation?

A

Dnmt3a & Dnmt3b

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20
Q

Which DNMTs are used in maintenance methylation (whilst cell divides)

A

Dnmt1

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21
Q

What do Tet enzymes do?

A

Convert 5-mC (5-Methylcytosine) into 5-hmC

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22
Q

By what process does 5-hmC get converted into thymine?

A

Deamination

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23
Q

Explain CpG methylation occurrence

A

Occurs usually at a Cytosine followed by Guanine base

Palindromic Motif – C then G from 5’ to 3’ on both strands = CpG dinucleotide

Majority of CpGs are sparse and methylated

Silencing large regions of the genome

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24
Q

What percentage of CpGs are clustered in gene promotors

A

7% - these are refered to as CpG islands

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25
Q

What percentage of genes have CpG islands?

A

50%

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26
Q

Explain how methylation of CpG islands is used in control of gene expression (in a normal cell)

A

Housekeeping genes that are transcribed a lot in the cell are not methylated- so that RNA Pol can make contact with the promoter, and gene transcription can occur

Also genes that we don’t want transcribed all the time e.g. time dependent, cell dependent/ need to be able to switch genes on and off. The CpG islands in these gene promotors can be methylated so RNA Pol cannot bind (this can be turned on and off depending on when you want the genes transcribed, in terms of development and response to stimulus)

X inactivation also due to methylation: Two x chromosomes in female, cant have all switched on at same time, methylation used to switch off the X chromosome not being used

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27
Q

Explain what happens when there is faulty methylation of CpG islands

A

cancer we get methylation of gene promotor of e.g. protective genes against cell replication

Sites can also be methylated due to environmental influences

Or we can get inappropriate removal of the methylation at certain gene sites, so that we get gene expression e.g. cancer oncogenes being transcribed

FDG – faulty methylation of genes that control growth

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28
Q

Methylation of cpg islands involved in:

A

– Cell-Specific Differences in Transcription

– Developmental Differences in Transcription

– Genomic imprinting - certain genes controlled throughout development due to their methylation pattern

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29
Q

What are the two processes where DNA methylation is critical?

A

variable in different tissues and involved in regulating tissue-specific gene expression patterns

permanently ‘imprinted‘, therefore maintained and memorised in (nearly) all tissues

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30
Q

Which genes don’t undergo demethylation when fertilisation occurs

A

Imprinted genes

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31
Q

Explain a graph that shows methylation against developmental time

A

Methylation marks are erased in primordial germ cells (PGCs).

Oocyte and sperm continue to re-aquire methylation marks until/during maturation yet in different time frames and to different extents.

Following fertilization demethylation of the genome occurs (accept imprinted genes) - Demethylation of paternal genome occurs at a fatser rate than maternal

Re-methylation begins at the blastocyst stage in a cell- type specific manner (ICM vs TE)

Carried out by Dmnt3a and Dmnt3b

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32
Q

What factors lead to epigenetic drift

A

Intrinsic and environmental factors

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33
Q

Explain the principle of the battle of the sexes in imprinting

A

Genes that promote fetal and placental growth are maternally imprinted (to secure the survival of the mother)

Genes that inhibit fetal and placental growth are paternally imprinted (to secure passing on of the father‘s genes at cost of the mother)

  • usually balanced correctly to make normal size baby
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34
Q

What does maternal imprinting do?

A

maternal imprinting limits use of maternal resources

by baby in utero

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35
Q

What does paternal imprinting do?

A

paternal imprinting maximizes use of maternal resources by baby in utero

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36
Q

Define imprinting

A

A process that leads to the heritable silencing of a gene on one of the parental chromosomes.

37
Q

Explain regulation of imprinting

A

Methylation of regulatory regions on one of the parental chromosomes (differentially methylated regions, DMRs or imprinting control regions, ICRs)

38
Q

Explain imprinting

A

Inherit 2 copies of each gene - one maternal, one paternal

only one expressed, other silenced by methylation (this is the one that is imprinted)

39
Q

Does imprinting refer to the gene that is silenced or the gene that is expressed?

A

Silenced

40
Q

Altered placental imprinted gene expression leads to…

A

FGR

41
Q

What do DMRs and ICRs stand for

A

DMR: differentially methylated regions

ICRs: imprinting control regions

42
Q

Explain how paternal imprinting leads to normal fetal and placental growth

A

Genes that inhibit fetal and placental growth are paternally imprinted (methylated)

= switch off inhibition of growth to increase growth

maternal genes are not methylated (and these reduce growth)

so therefore balance

43
Q

Explain what happens in hypomethylation in paternal imprinting

A

Paternal DMRs/ICRs are not methylated, and thedore both maternal and paternal genes are causing reduced growth, and therefore theres reduced growth

44
Q

Explain what happens in hypermthylation in paternal imprinting

A

Not just the paternal ICR/DMR, but also the maternal ICR/DMR, are methylated, and there is therefore increased growth

45
Q

Give an example of a gene that is imprinted and how it works

A

The imprinted insulin –like growth factor 2 (IGF2) gene

-Matches placental nutrient supply to fetal demand

-Altered IGF2 expression related to FGR

Insulator binds maternal unmethylated ICR1
–H19 gene expressed
–Blocks IGF2 expression

Paternal methylation at ICR1
–prevents CTCF binding
–IGF2 is expressed

46
Q

explain how a change in the H19/Igf2 imprint loop leads to loss or gain of Igf2 expression

A

Loss:
Neither maternal or paternal methylated at ICR1, H19 expressed, CTCF insulator can bind, and the enhamcer cannot reach Igf2 to help express it

Gain:
Noth maternal and paternal methylated at ICR1, H19 is not expressed and the CTCF insulator cannot bind, meaning the enhancer can bind to Igf2 and help express it

47
Q

What is Igf2

A

a major fetal GF involved in differentiation, organogenesis and metabolic regulation

48
Q

Give an example of a disorder caused by loss of imprinting at the Igf2/ICR1/H19 domain

A

Silver-Russell syndrome

49
Q

what are two imprinting disorders and what do they cause?

A

Silver-Russell syndrome

-Prenatal growth failure

-Loss of imprinting at the IGF2/ICR1/H19 domain

Beckwith-Wiedemann syndrome

-Prenatal over growth (macrosomia)

-Abnormally large offspring observed after in vitro production or manipulation of farm animal embryos.

-Gain of methylation of IC1 on the maternal chromosome

50
Q

what effects did in vitro culture have on mouse embryos

A

reduced methylation and specific imprinted sites, had effect on gene expression and number of cells at the blastocyst stage

51
Q

Explain an experiment that compared different media used for embryo culture in IVF

A

Market-Velker et al. 2010

  • mouse models
  • showed that mediums effected methylation of imprinted genes
  • in vivo:
    H19: 82% hypermethylation
    Snrpn: 92% ^
    Peg3: 100%
  • commercial media that effected hypermethylation least: KSOM
    H19: 75%
    Snrpn: 73%
    Peg3: 93%
  • comercial media that effected hypermethylation most: Whitten’s
    H19: 61%
    Snrpn: 58%
    Peg3: 54%
52
Q

Explain how placental-specific IGF-II is a major modulator of placental and fetal growth

A

Constância et al 2002

Mouse fetuses in which the Igf2 gene has been completely deleted weigh ≈60% of wild-type fetuses.

Deletion of the Igf2 gene transcript (P0) specifically expressed in the placenta leads to fetal growth restriction

compared gestational age to Placental weight and also compared gestational age to fetal weight

compared F/P weightvratios to gestational age

(all on graphs)

saw that:

Deletion of the Igf2 gene transcript (P0) specifically expressed in the placenta.

Leads to reduced growth of the placenta.

Followed several days later by fetal growth restriction.

= Greater fetal/placental ratio

53
Q

explain why the fetus weight didnt decrease to start with when Igf2 is deleted

A

smaller placenta is able to compensate and provide for fetus, by end of gestation, fetus is also smaller

54
Q

Explain simply how a relaxed vs condensed structure of chromatin effects TFs

A

Relaxed structure = activation of transcription Access for Transcription Factors

Condensed structure = inhibition of transcription No access for Transcription Factors

55
Q

Explain the degree of compaction of linear DNA

A

– 1:6 for nucleosomes

– 1:36 for the 30 nm fibre

– >1 :10 000 for the metaphase chromosome

56
Q

What is chromatin

A

-Complex of DNA & Histone Protein in Chromosomes

-Basic Structural Unit = Nucleosome

57
Q

Explain the structure of the nucleosome core particle

A

DNA

~147 base pairs

-Wraps 1.67 left-handed super helical turns

-Negatively charged

Histone Core Octamer

-Histone = Small highly conserved basic protein (positive charge)

-102–135 amino acids

= 2 copies of each core histone: H2A, H2B, H3, H4

= 2 H2A-H2B dimers & 1 H3-H4 tetramer

-Histone H1 linker molecule

Histone N-terminals = histone tails

  • Extend out of the core nucleosome
  • Subject to modifications
58
Q

What histone modifications mainly effect histone structure

A

Histone 3 & 4

59
Q

Explain histone tail modifications

A

Histone N-terminus = histone tail

Subject to modifications at different positions on different amino acids

most common is lysine (K)

modifications include:
-Acetylation
-Methylation
-phosphorylation

60
Q

Explain acetylation of histones

A

Acetylation site on histones, leads to activation through repelling interaction between histones, pushing them apart

61
Q

What are the three types of histone modifiers:

A

Writers
erasers
readers

62
Q

What do the histone modifiers writers do? give examples

A

add groups e.g. HATs, HMTs (histone methyl transferases)

63
Q

What do the histone modifiers erasers do? give examples

A

Erasers: remove groups e.g. HDATs KDM (lysine demethylase)

64
Q

What do the histone modifiers readers do?

A

molecules that read and recognise the mark, and bind

65
Q

What does methylation level of DNA also impact?

A

how stuck DNA is to histones

66
Q

When it comes to histone modifications, what makes good drug targets?

A

Histone modifiers (enzymes) - writers, erasers, readers

67
Q

Explain features of histone tails

A

-Post-Translational Modifications

-Influence Gene Expression

-Activating Marks

-Repressive Marks

68
Q

Explain effects/features of histone tail modifications

A

-Create or Prevent binding of Chromatin Remodelling Factors

-Influence Nucleosome mobility & function

-Scaffold for the recruitment of regulatory proteins

69
Q

Marks/changes to the histone tail are sometimes referred to as…

A

The histone code

70
Q

Explain how methylation of different residues of histone tails can lead to activation or repression

A

H3 tail:
- methylation of K4 = activating
- methylation of K9 and K27 = repressing

71
Q

What is a common histone tail mark

A

Acetylation of K27 - activating
often used to check if chromatin is in active state

72
Q

Give examples of activating/repressive marks and what the mark codes stand for

A

Active:
H3k4me2
H3K9ac
H3K27ac

Repressive:
H3k27me3
H3k9me3

H3 - histone 3
K—number - lysine residue and position of residue
me2 = dimethylation
me3 = trimethylation
ac = acetylation

73
Q

What do CxxC domain proteins do?

A

Read where CG islands are in the genome and bind, ensure genome gets transcribed by modifying epigenetic structure, adding or removing marks

74
Q

When can CxxC domain proteins bind CpGs?

A

When in unmethylated state

75
Q

What are MBPs

A

Methyl binding proteins

76
Q

Give an example of a CxxC domain protein, that is not an enzyme, and the enzyme complex it associates with

A

CFP1 (not enzyme) physically associates with the enzyme complex SET1
Adds mark – methylation at histone H3 position 4 in tail
causing a permissive state - switching on gnes

77
Q

Give an example of a CxxC domain protein that is an enzyme

A

KDM2A = lysine specific demethylase 2A
Removes mono/di methylation on histone H3 at lysine 33
These marks block the transcriptional machinery from binding
Modifying chromatin structure
Opening up - Making ‘landing sites’
causing permissive state - switching on genes

78
Q

Give an example of a CxxC domain protein which causes a restrictive state (switching off genes)

A

KDM2B binds at CG islands
KDM2B associates with the polycomb protein repressive complex = PRC1
KDM2B guides PRC1 to the CG island creating the restrictive chromatin state

79
Q

What proteins are responsible for gene silencing

A

Polycomb group proteins (PcG)

80
Q

What are the two main complexes of PcGs

A

Polycomb-repressive complex 1 and 2 (PRC1 & PRC2)

work independently or together
PRCs mediate gene silencing and x-inactivation

81
Q

Explain what PCR2 does

A

PCR2 catalyses tri-methylation at H3K27 via EZH2

Functional link with HDAC and DNMT

82
Q

Whats do methyl binding proteins do?

A

bind to methylated sites, read DNA and identify sites where genome needs to be shut down

83
Q

Give an example of an MBP

A

meCP2

84
Q

Give an example of a X inactivation disease

A

Retts syndrome

85
Q

Explain features of Retts syndrome

A

neurodevelopmenal disorder that affects girls.

Characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability.

Life expectancy ~ 40 years

No effective treatment

gene mutated = meCP2 (an MBP) - specifically abundant in neurones

86
Q

explain how Retts syndrome is an X inactivation disease

A

Mutated gene = meCP2

gene found on the X chromosome so no males with Retts as they die

87
Q

Explain the two different domain mutations that lead to Rett syndrome

A

Missense mutation in MBD (methylated DNA binding domain) - faulty protein and cannot identify methylated DNA and therefore cannot bind
(residues 100-150 roughly)
misssense in a second domain that binds the protein partner which is the HDAC complex, therefore this cannot bind and as this is what silences genes, this doesn’t occur (residues 302-306)

88
Q

Explain how mutations in meCP2 actually lead to symptoms in Retts syndrome

A

Histone H1 affected
Epigenome is disorganised
Specific gene expression up; others /down/unchanged
Effects transposons

Mouse model showed that this caused:
- Reduced brain size
- smaller neurones - less complex
- no cell death

BIOL3017 - Molecular and structural basis for disease (6 decks)

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