Imprinting

Question 1

Epigenetics

Answer 1

Mitotically and mieotically heritable variations in gene expression that are not caused by changes in DNA sequence

Question 2

What are examples of epigenetic mechanisms that alter chromatin structure - thereby affecting gene expression?

Answer 2

Reversible, post-translational modification of histones

DNA methylation

Question 3

Compact chromatin is characterized by?

Answer 3

DNA methylation and respressive histone marks

Question 4

Open chromatin (active) is characterized by?

Answer 4

Less DNA methylation and

Transrcriptional Complexes

Question 5

What does DNA methylation mediate?

Answer 5

Genetic transcription

Mainly through gene silencing

Question 6

What kind of sequences are methylated?

Answer 6

CpG islands

Question 7

What does having CpG islands methylated result in?

Answer 7

Recruitment of silencing complex
Histone deacetylation
Histone methylation 
Chromatin compaction 
Transcriptional repression

Question 8

What protein recognizes / interacts with methylation to promote gene silencing

Answer 8

MeCP2

Question 9

Does DNA methylation ever activate gene expression?

Answer 9

In some cases - developmentally programmed 3’CpG island methylation confers tissue-and cell-type specific transcriptional activation

Question 10

How can DNA methylation (which normally modulates gene silencing) activate genetic transcription?

Answer 10

In certain instances it can block proteins that silence gene expression

Question 11

What is genetic imprinting?

Answer 11

Sex-dependent, epigenetic modulation of regulatory regions such as promoter sequences
i.e. - Depending if male or female you have certain genes activated or silenced because of DNA methylation

Question 12

What mediates imprinting?

Answer 12

DNA methylation

Question 13

Is imprinting propagated through generations?

Answer 13

Yes, through generations so that genes inherited paternally will have the same pattern of expression as dad, and genes inherited maternally will have the same pattern of expression as mom

Question 14

What is the consequence of imprinting being propagated through generations

Answer 14

Genes maternally inherited will have same expression in progeny as in mom
Genes paternally inherited will have same expression in progeny as in dad

Question 15

What percent of the genes in the genome are thought to be imprinted

Answer 15

10%

Question 16

What epigenetic mark mediates genetic imprinting?

Answer 16

DNA methylation

Question 17

When are DNA methylation marks (patterns) first established?

Answer 17

In the gamete

Question 18

What happens with DNA methylation in somatic cells?

Answer 18

DNA methylation is stably maintained in somatic cells after fertilization

Question 19

Is DNA methylation reversible?

Answer 19

DNA methylation is reversible so that it can be reset during gametogenesis to transmit the appropriate sex-specific imprint to progeny

Question 20

What propagates epigenetic marks in somatic cells?

Answer 20

Maintenance methyltransferase

Question 21

What is the intermediate in DNA replication somatic cells during methylation maintenance?

Answer 21

A hemi-methylated dsDNA - i.e. the newly synthesized strand (from semi-conservative replication) will not have methylation marks until maintenance methyltransferase adds them

Question 22

What occurs with epigenetic marks in germs cells?

Answer 22

Epigenetic reprogramming occurs in germ cells

• there is erasure (demethylation) of chromosomes
• then depending on whether sperm or oocyte, you have establishment of new epigenetic marks - sex specific methylation

Question 23

Epigenetic memory

Answer 23

System somehow knows that in Dad you have methylated region A (meaning that all sperm will have methylated region A) and in mom you have methylated region B (meaning all oocytes will have methylated region B)

Question 24

What happens with imprinted regions in somatic cells?

Answer 24

Somatic maintenance of imprinted regions occurs in somatic cells

Question 25

What would happen if there was not an epigenetic "resetting" in gametogenesis?

Answer 25

There would be a high frequency of embryos with no active / or two active copies of imprinted genes (i.e. you could have gene A silencing in both oocyte and sperm and thus no functional gene A in embryo and double the activity of gene B)

Question 26

Prader Willi syndrome | CAUSE?

Answer 26

del(15q11-q13) on paternal chromosome Thus you are not expressing genes that are normal unmethylated in Dad and methylated in Mom because Dad's are absent and mom's are methylated

Question 27

What characterizes (Clinically) PWS?

Answer 27

Excessive eating short stature Hypogonadism Some degree of intellectual disability

Question 28

Angelman Syndrome | CAUSE?

Answer 28

del(15q11-q13) on maternal chromosome Thus, you are not expressing maternal genes that should be active in this region and you are not expressing them from the father chromosome either because it has been silenced

Question 29

Angelman Syndrome | Clinical?

Answer 29

Short stature severe intellectual disability spasticity seizures

Question 30

del(15q11-q13) Maternal -->

Answer 30

Angelman syndrome

Question 31

del(15q11-q13) Paternal -->

Answer 31

Prader Willi Syndrome

Question 32

What creates the DNA methylation program for sex specificity in chromosomes?

Answer 32

Imprinting Center (modulated by DNA methylation) dictates the sex specific expression of the imprinted genes

Question 33

What is responsible for 70% of Prader Willi Cases?

Answer 33

70% are caused by deletion of paternal chromasome - thus you only have expression of maternal genes (as paternal are methylated on maternal chromosome)

Question 34

What is responsible for 28% of Prader Willii Cases?

Answer 34

28% are due to two chomosomes with sex specific maternal imprint --> (Maternal uniparental disomy - this can occur when trisomic conceptus undergoes trisomy rescue

Question 35

What is responsible for 2% of Prader Willi Syndrome?

Answer 35

2% is due to mutation on imprinting center on the paternal allele so that it receives the maternal imprinting patterns

Question 36

What were the two paternally expressed genes we focused on?

Answer 36

SNRPN | IPW

Question 37

What was the maternally expressed gene we focused on?

Answer 37

UBE3A

Question 38

Absence of expression of SNRPN results in?

Answer 38

PWS

Question 39

Absence of expression of UBE3A results in?

Answer 39

AS

Question 40

What is responsible for 70% of Angelman syndrome cases?

Answer 40

Deletion of maternal 15q11-13

Question 41

What is responsible for 4% of AS

Answer 41

Paternal Uniparental disomy - Trisomy rescue This is interesting - I wonder why retains female copy more frequently?

Question 42

What two errors are responsible for 8% of AS, each?

Answer 42

Imprinting center mutation --> paternal pattern of imprinting (silence of madre) or Mutation of UBE3A gene on maternal allele

Question 43

What is responsible (usually) for the deletions in the PWS/AS region of chromosome 15?

Answer 43

Deletions result from the presence of low copy repeats in the vicinity of the common breakpoints The repeats are derived from genomic duplications of HERC2 The repeats flanking 15q11q13 may be involved with inter and intrachromosomal misalignment and homologous recombination resulting in deletions

Question 44

At a basic level, just know that deletions are cause by...

Answer 44

low copy repeat misalignment

Question 45

PWS and AS can result from uniparental Disomy - what is this?

Answer 45

Trisomic conceptus --> | Mitotic nondisjunction event early in gestation rescues lethality (trisomy rescue)