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Concepts of Disease > Epigenetics > Flashcards

Epigenetics Flashcards

1
Q

Define epigenetics

A

Epigenetics is the study of heritable changes in genome function that occur without a change in DNA sequence.

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2
Q

What are the 3 DNA methyltransferases?

A

DNMT1
DNMT3a
DNMT3b

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3
Q

What is meant by DNA methylation is symmetrical?

A

DNA methylation occurs on both the sense strand and antisense strand.

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4
Q

What are the characteristics of CpG islands?

A

0.5-2kb in size.
Commonly located at the 5’ end of many genes often overlapping with the promoter and 1st exon.
56% human genes and 47% mouse genes have a CpG island over their promoter.

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5
Q

What are the two ways that DNA methylation regulates gene expression/promotes gene silencing?

A
  1. The methyl group changes the recognition seuqence by preventing proteins binding e.g. CTCF or by allowing binding of certain proteins e.g. Kaiso.
  2. Methylation attracts methyl-binding domain proteins which recruit protein complexes that modify histones.
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6
Q

Which DNA methyltransferases are de novo methyltransferases?

A

DNMT 3a

DNMT 3b

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7
Q

How is DNA methylation inherited between cell generations?

A

DNA methylation is re-established at CG motifs in daughter strands by recruiting the maitenance DNA methyltransferase DNMT1 to the replication fork by UHRF1 and PCNA.
DNMT1 specifically methylates hemi-methylated DNA methylating the opposite strand restoring symmetrical DNA methylation.

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8
Q

How are methyl groups removed?

A

TET proteins are responsible for the active removal of methyl groups, they oxidise methyl cytosine into products which are recognised and repaired back to cytosine by base excision repair (BER).

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9
Q

What are the two proposed mechanisms by which histone modifications can be epigenetic?

A
  1. After DNA replication, the methylated nucleosomes are distributed equally to the two daughter strands and this re-establishes the marks that were previously there.
  2. After DNA replication, the modified histones are lost but the methyltransferase complex is retained at the replication fork and so as DNA is replicated, new histones are brought in and modified.
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10
Q

How many genes are found on the X chromosome?

A

3000

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11
Q

How many genes are found on the Y chromosome?

A

30

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12
Q

From where is Xist expressed?

A

The X-inactivation centre on the X chromosome to be inactivated.

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13
Q

When is Xist expressed?

A

Xist is expressed at the 4-8 cell stage after fertilisation.

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14
Q

Which histone variant becomes enriched on the Xi?

A

macroH2A

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15
Q

What happens to the CpG islands on the Xi?

A

They acquire DNA methylation.

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16
Q

What are the features of the Xa?

A

Histone tails are acetylated.
H3K4 methyalted in promoters.
Variants H3.3 and H2Abb become enriched.
Polycomb histone modifications only occur at silent loci.
Gene promoters are depleted of DNA methylation.
DNA methylation in gene bodies.

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17
Q

What are the features of the Xi?

A 
Histone tails hypo-acetylated. 
H3K4 methylation depleted. 
Polycomb histone modifications enriched. 
Variant histone macroH2A enriched. 
DNA methylation of gene promoters.
Hypo-methylation of gene bodies.
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18
Q

What histones variants are enriched on the Xa?

A

H3.3 and H2Abb

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19
Q

……..mendelian diseases are linked to mutations in …….. X-lined genes

A

168 mendelian diseases are linked to 113 X-linked genes.

20
Q

What is the frequency of DMD?

A

15 per 100000 males.

21
Q

What is the frequency of haemophilia A?

A

5 per 100000 males.

22
Q

What is the frequency of hyphohidrotic ectodermal dysplasia?

A

1 per 100000.

23
Q

Name 3 X-linked recessive diseases?

A

Haemophilia A
Duchenne Muscular Dystrophy
Hyphohidrotic ectodermal dysplasia.

24
Q

In a benign ovarian teratoma, all 46 chromosomes are what?

A

Of maternal origin.

25
Q

What causes a benign ovarian teratoma?

A
  1. Failure of meiosis I
  2. Failure of meiosis II
  3. Endoduplication of the haploid ovum
26
Q

What causes a hydatidiform mole?

A

Fertilisation of an empty oocyte by 2 sperm.

Fertilisation of an empty oocyte by 1 sperm followed by duplication of the haplodi sperm pronucleus.

27
Q

Why can’t monoparental mammalian embryos develop?

A

0.4% of mammalian protein-coding genes are monoallelically expressed due to the phenomenon of genomic imprinting.
This means some genes are exclusively expressed from either the maternal or paternal allele - there is gene silencing of the other allele by DNA methylation.

28
Q

What % of human protein-coding genes are monoallelically expressed?

A

0.4%

29
Q

In terms of genomic imprinting, describe the ovarian teratoma?

A

The ovarian teratoma has 2 maternal genomes.
The bilallelically expressed genes are expressed entirely normally.
There is a loss of expression of paternally expressed genes.
There is a gain of expression of maternally expressed genes.

30
Q

In terms of genomic imprinting, describe the hydatidiform mole?

A

The hydatidiform mole has 2 paternal genomes.
The biallelically expressed genes are expressed normally.
There is a loss of expression of maternally expressed genes.
There is a gain of expression of paternally expressed genes.

31
Q

Name a real life imprinted domain?

A

11p15 contains several imprinted genes including CDKN1C, H19 and IGF2.

32
Q

Which reciprocal imprinting disorders arise from errors in the imprinted domain at 11p15?

A

Beckwith Weidemann Syndrome

Silver Russel Syndrome

33
Q

Describe Beckwith Weidemann syndrome?

A

Beckwith Weidemann Syndrome is a fetal overgrowth syndrome affecting 1 in 13700.
BWS describes babies born in the 95th weight percentile.
Characteristics include macroglossia omphalocoele (abdominal wall defects), predisposition to Wilm’s tumours, cleft palate, placentomegaly, neonatal hypoglycaemia.
BWS is a genomic imprinting disorder.
Some BWS patients have paternal disomy of 11p15.

34
Q

What are the genetics underlying Beckwith Weideman syndrome?

A

Paternal disomy of 11p15.
This results in double the expression of IGF2 and loss of expression of CDKN1C and H19.
These patients have both genetic and epigenetic alterations.
The most common alteration is loss of DNA metylation at the imprinting centre KvDMR - results in biallelic expression of paterally expressed gene LIT1.

35
Q

What is the most common alteration seen in BWS?

A

Loss of DNA methylation at the imprinting centre KvDMR of the 11p15 imprinted domain.

36
Q

What is the imprinting centre of the 11p15 imprinted domain?

A

KvDMR

37
Q

Describe Silver Russel Sydrome?

A

Silver Russel Sydrome is a fetal imprinting growth restriction disorder affecting 1 in 100,000.
Low birth weight - born below the 5th weight percentile.
They are born small and underweight and remain small throughout development - poor postnatal growth.
Classic facial phenotype, triangular face, small chin, asymmetrical growth, lack subcutaneous fat, night sweats and hypoglycaemia.
Maternal disomy of 11p15.

38
Q

Define the term sydrome and list two?

A

A syndrome is a disease with a number of elements which are seemingly unrelated.
Beckwith Weidemann Syndrome.
Silver Russel Syndrome.

39
Q

What are the genetics underlying SRS?

A

There are 2 copies of maternal genes, there is loss of paternally expressed genes.
There is twice as much CDKN1C and H19 and loss of IGF-2 expression.
SRS is linked to many alterations both genetic and epigenetic.
Some SRS patients have microduplications and hypermethylation.

40
Q

What is different between the pattern of inheritance of a genomic imprinting disorder compared to an X-linked disorder?

A

Genomic imprinting disorders when inherited (very rare, most are de novo) show sex-specific transmission but not sex-specific inheritance.

41
Q

Which disorders map to the locus 15q11-13?

A

Prader-Willi syndrome and Anglemann Syndrome.

42
Q

How many are affected by Friedrich’s ataxia?

A

1-2 per 100,000.

43
Q

What causes Friedrich’s ataxia?

A

Mutation in the frataxin gene at 9q13 results in expansion of GAA repeat within the first intron.
This expansion is associated with DNA methylation thus silencing the gene.
Normal individuals have 8-33 copies of the GAA repeat.
Affected individuals have 600-900 copies of the GAA repeat.

44
Q

What is Horvath’s clock?

A

An epigenetic age estimator based on sequencing the methylated genome.

45
Q

What is the frequency of schizophrenia?

A

1 in 100

46
Q

What is the concordance rate of schizophrenia between monozygotic twins?

A

50%

47
Q

Name 2 epidrugs?

A 
5-azacytidine (Vidaza) a drug that demethylates DNA. 
superanilohdroxamic acid (Vorinostat) a HDAC inhibitor.

Concepts of Disease (11 decks)

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