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BIOL2017- Molecular Structural Basis of Disease > Epigenetic's and disease > Flashcards

Epigenetic's and disease Flashcards

1
Q

Can the placenta contribute to poor Fetal growth? T/F

A

True

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2
Q

What can cause Fetal growth restriction?

A

Chromosomal defects,

Placental insufficency,

Enviroment (smoking, multiple gestation, alcohol, drug abuse etc)

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3
Q

Why is early fetal development important?

A

utero development builds foundations and poor development in utero can cause health disorders later on in life such as increased risk of heart disease.

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4
Q

What are some risks associated with fetal growth restriction (FGR)

A

can lead to risk of death or illness.

babies can be stillborn, at risk of developing lifelong disabilities such as cerebral palsy.

at risk of developing non communicable diseases in adulthood.

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5
Q

What did the Dutch Hunger winter of 1944/45 tell us about the need of adequate nutrition in fetal development?

A

nutrient derivation leads to smaller babies being birthed and they are seen have increased risk of developing CV diseases and increased risk of diabetes.

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6
Q

What can levels of gene expression be used for to predict?

A

based on gene mRNA level expression there can be prediction of the size of the baby.

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7
Q

What vitamin can have strong impacts on the development of babies?

A

Vitamin D

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8
Q

what can altered epigenetics tell us about a babies development?

A

can control gene expression and help us understand how a baby will be at risk of disease as they grow.

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9
Q

what is the epigenome?

A

the genome wide epigenetic state including all the epigenetic modifications within the cells genome.

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10
Q

what is an epigenetic tag?

A

epigenetic marks or modifications

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11
Q

what are epigenetic modifiers?

A

enzymes that catalyse the addition or removal of epigenetic tags.

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12
Q

what are common epigenetic mechanisms?

A
  1. Chemical modifications (DNA methylation)
  2. Post translational modifications of histone tails.
  3. Histone variants.
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13
Q

What is the most common methylation of DNA?

A

Cytosine (CpG) is methylated to 5-methyl cytosine (5mC)
it is the most common and stable and has no effect on base pairing.

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14
Q

what enzyme catalyses DNA methylation

A

DNA methyltransferase. (Dnmt)

De- novo methylation is done by Dnmt3a and Dnmt3b
maintance of methylation is done by Dnmt1

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15
Q

What is de novo methylation?

A

De novo methylation is the process of adding methyl groups to previously unmethylated CpG dinucleotides in DNA.

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16
Q

What enzymes are involved in de novo methylation?

A

DNMT3A, DNMT3B, and DNMT3L are the three main DNA methyltransferases involved in de novo methylation.

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17
Q

When does de novo methylation occur?

A

De novo methylation occurs primarily during early development and in germ cells, where it is essential for establishing epigenetic marks that are passed on to the next generation.

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18
Q

What is the de novo methyltransferase complex?

A

The de novo methyltransferase complex is a complex of proteins that includes DNMT3A/B and other cofactors such as UHRF1 and PCNA. It recognizes and binds to specific sequences in DNA and catalyzes de novo methylation.

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19
Q

What is the function of maintenance methylation?

A

The function of maintenance methylation is to preserve the epigenetic marks of DNA methylation that are established during de novo methylation, by adding methyl groups to hemimethylated CpG sites after DNA replication.

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20
Q

What is the enzyme responsible for maintenance methylation?

A

DNMT1 is the enzyme responsible for maintenance methylation.

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21
Q

How does DNMT1 recognize its target sites for maintenance methylation?

A

DNMT1 recognizes and binds to hemimethylated CpG sites through its two DNA-binding domains.

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22
Q

What are the consequences of aberrant de novo methylation?

A

Aberrant de novo methylation can contribute to various diseases, such as cancer, where it can lead to silencing of tumor suppressor genes or activation of oncogenes.

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23
Q

What factors can affect the regulation of the maintenance methylation pathway?

A

Chromatin structure and DNA sequence context can affect the accessibility and activity of DNMT1 at specific CpG sites.

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24
Q

What are CpG islands?

A

Regions of DNA that are rich in CpG dinucleotides, often found within gene promoter regions.

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25
Q

What is CpG island promoter repression?

A

The epigenetic silencing of gene expression that occurs when CpG islands within gene promoter regions become densely methylated.

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26
Q

What enzymes are associated with CpG island promoter repression?

A

DNA methyltransferases, including DNMT1, DNMT3A, and DNMT3B.

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27
Q

What factors can influence CpG island promoter repression?

A

Environmental exposures, genetic variations, and cellular signaling pathways.

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28
Q

Why is understanding CpG island promoter repression important?

A

It is important for developing effective therapies for diseases associated with aberrant gene silencing, such as cancer.

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29
Q

What is X-inactivation?

A

The process by which one of the two X chromosomes in female cells is inactivated to achieve gene dosage compensation between males and females.

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30
Q

What is the mechanism of X-inactivation?

A

The inactive X chromosome is silenced through the addition of repressive epigenetic marks, such as histone modifications and DNA methylation.

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31
Q

What is the significance of X-inactivation in epigenetics?

A

X-inactivation is an important example of epigenetic regulation and provides insights into how epigenetic modifications can regulate gene expression and be stably maintained through cell divisions. Aberrant X-inactivation can lead to various disorders, including X-linked diseases.

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32
Q

What is imprinting?

A

A form of epigenetic regulation where gene expression is dependent on the parent of origin, which is mediated by DNA methylation. Aberrant imprinting can lead to developmental disorders, including Beckwith-Wiedemann syndrome and Angelman syndrome.

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33
Q

what occurs in regard to methylation of primordial germ cells (PGCs)

A

methylation marks get erased and then oocyte and sperm continue to re acquire methylation marks during their maturation. this occurs at different time frames and to different extents

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34
Q

what occurs to the methylation of genome following fertilisation?

A

Demethylation. all methylation marks are removed and the imprinted genes are accepted.

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35
Q

What occurs to the methylation at the blastocyst stage?

A

re methylation occurs in a cell type specific manner. (ICM vs TE) which is carried out by DNMT3a/b

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36
Q

What is maternal imprinting?

A

Maternal imprinting refers to the expression of a gene from the maternal allele and silencing of the paternal allele.

37
Q

What is paternal imprinting?

A

Paternal imprinting refers to the expression of a gene from the paternal allele and silencing of the maternal allele.

38
Q

How does DNA methylation regulate gene expression during imprinting?

A

Methylation of CpG islands within gene promoters can affect the accessibility of the promoter to transcription factors and RNA polymerase, leading to silencing or activation of gene expression.

39
Q

What are some examples of imprinted genes?

A

IGF2 is imprinted paternally and promotes fetal growth, while H19 is imprinted maternally and regulates IGF2 expression.

40
Q

What are the implications of disruptions in imprinting for human health?

A

Disruptions in imprinting can have profound effects on health and development, and have been linked to various disorders, including cancer, neurological disorders, and developmental syndromes.

41
Q

what is the definition of imprinting?

A

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

42
Q

What is altered placental imprinted gene expression?

A

Altered placental imprinted gene expression refers to changes in the expression of imprinted genes in the placenta, which can lead to abnormal fetal growth and development.

43
Q

How does altered placental imprinted gene expression contribute to fetal growth restriction (FGR)?

A

Imprinted genes play a critical role in regulating fetal growth and development, and disruptions in their expression can lead to abnormal placental development and function, impaired nutrient transport, and altered hormonal signaling. This can result in restricted fetal growth and lead to FGR, which is associated with increased risks of stillbirth, preterm delivery, and long-term developmental and health problems.

44
Q

What is Insulin-like growth factor 2 (IGF2) and what role does it play in fetal development?

A

IGF2 is a major fetal growth factor that regulates fetal growth, differentiation, and metabolic regulation.

45
Q

Which allele is the imprinted IGF2 gene expressed from?

A

The imprinted IGF2 gene is expressed from the paternal allele.

46
Q

Where is the IGF2 gene cluster found and disruption to it can cause what?

A

Found on the chromosome 11p15 and disruption to the normal imprinting patten can occur due to altered IGF2 expression from FGR.

47
Q

What is the IGF2 gene cluster and what does it include?

A

The imprinted IGF2 gene cluster includes the IGF2 gene, the lCR1/H19 domain, the crcF insulator, and the H19 gene.

48
Q

What is the function of the H19 gene in the IGF2 gene cluster?

A

The H19 gene is expressed from the maternal allele and blocks IGF2 expression.

49
Q

What is the role of the imprinting control region (ICR1) in the IGF2 gene cluster?

A

The imprinting control region (ICR1) is an insulator that binds to the maternal unmethylated ICR1 and prevents CTCF binding, allowing for IGF2 expression from the paternal allele.

50
Q

What is the H19/IGF2 imprint loop and why is it important?

A

The H19/IGF2 imprint loop is a regulatory mechanism that maintains the normal imprinting pattern in the IGF2 gene cluster. It is important for proper fetal growth and development.

51
Q

How can disruptions in the imprinting pattern of the IGF2 gene cluster lead to FGR?

A

Loss or gain of DNA methylation at differentially methylated regions (DMRs) on the maternal or paternal allele can disrupt the imprinting pattern and alter IGF2 expression, leading to FGR.

52
Q

What occurs when there is an imbalance of maternal and paternal imprinting?

A

leads to large or small baby

53
Q

What are mechanisms through which epigenetic modifications can occur?

A

-Chemical modifications of DNA
-post translational modifications of histone tails
-Histone variants

54
Q

What is Silver Russell syndrome?

A

Prenatal growth faliure. Loss of imprinting at the IGF2/H19 domain.

55
Q

What is Beckwith-Wiedemann syndrome?

A

Prenatal overgrowth. (Macrosomia)
leads to abnormally large offspring observed after in vitro production or manipulation of farm animal embryos.
There is a gain of methylation of IC1 on the maternal chromosome. (leads to the overexpression of IGF2 and other genes in the imprinted gene cluster)

56
Q

How can culture mediums in vitro affect methylation and imprinting genes?

A

Can alter the avalibility of nutrients and growth factors needed for development and epigenetic regulation. Study showed in suboptimal medium, Altered DNA methylation patterns on the H19 and IGF2 genes.

Reduced methylation on the maternal H19 allele which resulted in increased expression of the H19 gene and decreased expression of the IGF2 gene, from the paternal allele.

57
Q

overall what occurs in the methylation and gene expression of in vitro cultured blastocysts?

A

Reduced methylation —> leads to altered gene expression in trophoblast cells —-> that is H19 increased expression over IGF2 with decreased expression

58
Q

What is the role of placental-specific IGF-II in fetal growth?

A

is a major modulator of placental and fetal growth.

59
Q

When IGF2 gene is deleted from mouse foetuses what occurs to the mouse weight?

A

Complete deletion of IGF2 leads to mice weighing around 60% of the wild type.

60
Q

What does deletion of the IGF2 gene transcript (P0) (which is specifically expressed in the placenta) lead to?

A

Leads to fetal growth restriction. This is due to a reduced growth of the placenta. leads to a greater fetal/placenta ratio. To begin with the smaller placenta is able to compensate and provide for the foetus but by the end of gestation, foetus is smaller.

61
Q

What is chromatin and what degrees of condensation does it achieve?

A

It is the packing mechanism of the genome. It has varying levels of compaction.

-1:6 for nucleosomes. (where there are DNA wrapped around histones with a diameter of around 10nm)

-1:36 for the 30nm chromatin fibre where the nucleosomes are coiled together with a diameter of 30nm.

-1:10,000 for the metaphase chromosome which is formed from the further compacted 30nm fibres.

62
Q

In a nucleosome give me the details about the DNA?

A

approx 167 base pairs
wraps 1.67 left handed super helical turns
is negatively charged

63
Q

In a nucleosome give me the details about the histone core octamer.

A

Has a histone that is a small highly conserved basic protein with a positive charge.

Made of 102-135 amino acids.

is comprised of 2x copies of each of four types of core histones. H2A, H2B, H3 and H4.

has 2 dimers of H2A-H2B and a H3-H4 tetramer.

The octamer interacts with a linker molecule called Histone H1. plays roll in organising the chromatin.

64
Q

What is a histone Tail?

A

Is the Histones N terminals. they extend out of the core nucleosome and can be subject to modifications.

65
Q

What is histone code?

A

term used to describe the marks/changes to the tail.

66
Q

What are histone modifers?

A

can have :

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

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

Readers: molecules that read and recognise the mark and bind

67
Q

Methylation at different residues on the tails can lead to different outcomes. what residues on the H3 tail get methylated and what are their outcomes?

A

Methylation of K4 leads to activating

methylation of K9 and K27 leads to repression

(K is lysine)

68
Q

What are some common histone tail marks?

A

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

Active: H3K4me2, H3K9ac

repressive: H3K27me3, H3K9me3

(me2 is dimethylation, me3 is trimethylation and ac is acetylation)

69
Q

What are CpG dinucleotides?

A

Pairs of nucleotides in DNA where cytosine is followed by guanine. CpG dinucleotides can be methylated, which can influence gene expression.

70
Q

What are CxxC domain proteins?

A

Proteins that bind to unmethylated CpG dinucleotides. They promote transcriptional activation and help ensure proper gene expression.

71
Q

What are MBP proteins? (methyl binding protiens)

A

Proteins that bind to methylated CpG dinucleotides. They can lead to transcriptional repression and inhibit gene expression.

72
Q

What is CFP1? (CxxC finger protein 1)

A

A protein that associates with the enzyme complex SET1 and adds a methyl mark to histone H3 position 4 in the tail. This promotes a permissive state and can switch on genes.

73
Q

What is KDM2A? (lysine specific demethylase 2A)

A

A protein that removes mono/di methylation on histone H3 at lysine 33. This opens up chromatin structure and creates “landing sites” that promote a permissive state, allowing genes to be switched on.

74
Q

What is KDM2B?

A

A protein that binds at CG islands and associates with the polycomb protein repressive complex (PRC1). KDM2B guides PRC1 to the CG island, creating a restrictive chromatin state that switches off genes.

75
Q

What are Polycomb group proteins (PcG) responsible for?

A

gene silencing.

76
Q

What are the main PcG protein complexes?

A

PRC1 and PRC2 are the two main PcG protein complexes.

PRC2 adds a methyl group to histone H3 at lysine 27 (H3K27me3) (tri methylation)

PRC1 binds to the H3K27me3 mark and helps to maintain the repressive state.

77
Q

What is the role of PRC2 in histone modification?

A

PRC2 catalyzes the addition of a methyl group to histone H3 at lysine 27, specifically adding a tri-methylation mark known as H3K27me3. The enzyme responsible for this modification is EZH2. This modification is associated with a repressive chromatin state and leads to silencing of genes.

78
Q

PCR2 has a functional link with what?

A

HDAC and DNMT

79
Q

What is the functional link between PRC2 and HDACs?

A

PRC2 can physically interact with HDACs, leading to enhanced repressive activity of PRC2 and transcriptional repression. HDACs remove acetyl groups from histones, leading to a condensed chromatin structure and transcriptional repression.

80
Q

What is the functional link between PRC2 and DNMTs?

A

PRC2 can recruit DNMTs to specific regions of DNA, leading to DNA methylation and transcriptional repression. DNMTs add methyl groups to DNA, leading to a repressive chromatin state and silencing of genes.

81
Q

What is Rett syndrome

A

A neurological disorder that affects girls. it is characterised 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 of ~40 years. and no effective treatment.

82
Q

What is the mutated gene that leads to Rett syndrome?

A

MeCP2. it is not exclusively expressed in the brain (not a brain gene but is abundant in neurones). a basic housekeeping protein that reads DNA methylation.

83
Q

Why is Rett syndrome only in girls?

A

Located on the X chromosome so male dies.

Due to females having two X can use X inactivation as have one healthy MeCP2 gene. leads to expression of healthy one in some cells and mutated one in others.

compensates and leads to a milder form of the disorder. hence why males with Rett usually dont survive past infancy.

84
Q

What sort of mutation occurs in MeCP2?

A

its a missense mutation that produces a faulty protein that cannot identify methylated DNA.

85
Q

Why cant Rett syndrome be inherited?

A

people with Rett syndrome cannot reproduce.

86
Q

What is the second domain of the meCP2 protein and what does it do?

A

The second domain of the meCP2 protein binds to protein partners, including a histone deacetylase (HDAC) complex, which is involved in gene silencing.

87
Q

What happens when meCP2 binds to the HDAC complex?

A

When meCP2 binds to the HDAC complex, it leads to the removal of acetyl groups from histones, resulting in a more compact chromatin structure that makes it difficult for transcription factors to access the DNA and activate gene expression.

88
Q

What can happen when there are mutations in the meCP2 gene in regard to its interaction with HDAC complex?

A

Mutations in the meCP2 gene can disrupt the interaction between meCP2 and the HDAC complex, leading to disorganized epigenetic regulation of gene expression and abnormal expression of certain genes, while others may be silenced or unaffected. It can also affect the regulation of transposable elements, which are mobile genetic sequences that can disrupt normal gene function when they are activated

89
Q

In a mouse model what was seen wiht the loss of meCP2 function to study Rett syndrome?

A

Studies using mouse models of Rett syndrome have shown that the loss of meCP2 function can lead to reduced brain size and smaller, less complex neurons, although there is no evidence of cell death. This suggests that meCP2 plays an important role in regulating neuronal development and function.

BIOL2017- Molecular Structural Basis of Disease (3 decks)

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