Imprinting Flashcards
Epigenetics
Mitotically and mieotically heritable variations in gene expression that are not caused by changes in DNA sequence
What are examples of epigenetic mechanisms that alter chromatin structure - thereby affecting gene expression?
Reversible, post-translational modification of histones
DNA methylation
Compact chromatin is characterized by?
DNA methylation and respressive histone marks
Open chromatin (active) is characterized by?
Less DNA methylation and
Transrcriptional Complexes
What does DNA methylation mediate?
Genetic transcription
Mainly through gene silencing
What kind of sequences are methylated?
CpG islands
What does having CpG islands methylated result in?
Recruitment of silencing complex Histone deacetylation Histone methylation Chromatin compaction Transcriptional repression
What protein recognizes / interacts with methylation to promote gene silencing
MeCP2
Does DNA methylation ever activate gene expression?
In some cases - developmentally programmed 3’CpG island methylation confers tissue-and cell-type specific transcriptional activation
How can DNA methylation (which normally modulates gene silencing) activate genetic transcription?
In certain instances it can block proteins that silence gene expression
What is genetic imprinting?
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
What mediates imprinting?
DNA methylation
Is imprinting propagated through generations?
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
What is the consequence of imprinting being propagated through generations
Genes maternally inherited will have same expression in progeny as in mom
Genes paternally inherited will have same expression in progeny as in dad
What percent of the genes in the genome are thought to be imprinted
10%
What epigenetic mark mediates genetic imprinting?
DNA methylation
When are DNA methylation marks (patterns) first established?
In the gamete
What happens with DNA methylation in somatic cells?
DNA methylation is stably maintained in somatic cells after fertilization
Is DNA methylation reversible?
DNA methylation is reversible so that it can be reset during gametogenesis to transmit the appropriate sex-specific imprint to progeny
What propagates epigenetic marks in somatic cells?
Maintenance methyltransferase
What is the intermediate in DNA replication somatic cells during methylation maintenance?
A hemi-methylated dsDNA - i.e. the newly synthesized strand (from semi-conservative replication) will not have methylation marks until maintenance methyltransferase adds them
What occurs with epigenetic marks in germs cells?
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
Epigenetic memory
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)
What happens with imprinted regions in somatic cells?
Somatic maintenance of imprinted regions occurs in somatic cells
What would happen if there was not an epigenetic “resetting” in gametogenesis?
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)
Prader Willi syndrome
CAUSE?
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
What characterizes (Clinically) PWS?
Excessive eating
short stature
Hypogonadism
Some degree of intellectual disability
Angelman Syndrome
CAUSE?
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
Angelman Syndrome
Clinical?
Short stature
severe intellectual disability
spasticity
seizures
del(15q11-q13) Maternal –>
Angelman syndrome
del(15q11-q13) Paternal –>
Prader Willi Syndrome
What creates the DNA methylation program for sex specificity in chromosomes?
Imprinting Center (modulated by DNA methylation) dictates the sex specific expression of the imprinted genes
What is responsible for 70% of Prader Willi Cases?
70% are caused by deletion of paternal chromasome - thus you only have expression of maternal genes (as paternal are methylated on maternal chromosome)
What is responsible for 28% of Prader Willii Cases?
28% are due to two chomosomes with sex specific maternal imprint –> (Maternal uniparental disomy - this can occur when trisomic conceptus undergoes trisomy rescue
What is responsible for 2% of Prader Willi Syndrome?
2% is due to mutation on imprinting center on the paternal allele so that it receives the maternal imprinting patterns
What were the two paternally expressed genes we focused on?
SNRPN
IPW
What was the maternally expressed gene we focused on?
UBE3A
Absence of expression of SNRPN results in?
PWS
Absence of expression of UBE3A results in?
AS
What is responsible for 70% of Angelman syndrome cases?
Deletion of maternal 15q11-13
What is responsible for 4% of AS
Paternal Uniparental disomy -
Trisomy rescue
This is interesting - I wonder why retains female copy more frequently?
What two errors are responsible for 8% of AS, each?
Imprinting center mutation –> paternal pattern of imprinting (silence of madre)
or
Mutation of UBE3A gene on maternal allele
What is responsible (usually) for the deletions in the PWS/AS region of chromosome 15?
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
At a basic level, just know that deletions are cause by…
low copy repeat misalignment
PWS and AS can result from uniparental Disomy - what is this?
Trisomic conceptus –>
Mitotic nondisjunction event early in gestation rescues lethality (trisomy rescue)
