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summarise the implication for DNA methylation on transcriptional activity
DNA methylation inactivates the gene
where is DNA methylated to inactivate it?
mainly at specific CPG islands at the 5' end of the gene
- can be throughout tho
how perminant is DNA methylation in supressing a gene?
DNA methylation perminantly silences a gene
what does histone methylation do to transcriptional activity?
can either activate it or supress it depending on where the methylation is
what is the effect of methylating histone H3K9?
transcriptional supression - linked to heterochromatin
what is "H3K9"?
the lysine residue 9 on histone H3
which lysine residue do you want to methylate to activate a gene?
H3K4
what are microRNA? what celllular role do they play?
RNA molecules which arent translated into a protein but have functional activity needed for regulating gene transcription
what does methylation of cytosine on DNA create?
methylcytosine
does methylation of cytosine on DNA alter the sequence?
no just adds a methyl group
- methylcytosine is still cytosine
what is methylcytosine often refered to as?
the 5th base
- but aparently still not a sequence change says Laura
what are CpG islands?
palindromic sequences of CpG
- this just means that cytosine is sat next to quanine in the sequence
what can happen to CPG islands?
they can be methylated
what is the effect of cytosine methylation on transcriptional activity?
causes the chromatin to condense leading to silencing of the gene
what is the purpose of CpG islands?
allows for the methylation of the cytosine
comment on the PTM's present on euchromatin and its transcriptional activity
Euchromatin is transcriptionally active resulting from:
- High histone acetylation
- low DNA methylation
- H3-K4 methylation
comment on the PTM's present on heterochromatin and its transcriptional activity
heterochromatin is transcriptionally inactive resulting from:
- Low histone acetylation
- Dense DNA methylation
- H3-K9 methylation
does DNA methylation allow for fast switching on and off of genes?
no it perminantly inactivates them
what enzyme is responsible for replicating the methylation from the parent strand of DNA onto the daughter strand during DNA replication?
DNMT1 methylase
(short for DNA MethylTransferase 1)
what happens if an embryo doesnt have DNMT1?
itll die
does DNMT1 add new methyl groups on top of those present on the parent strand?
no it just maintains the origional ones
what are DNMT3A and DNMT3B responsible for?
adding De Novo methyl groups onto genes to change its transcription profile
when is DNMT3A and DNMT3B used? what genes do they methylate
when the cell is specialising so new methyl groups need to be added to pluripotent genes to switch them off
what happens if you dont get DNMT3a?
perinatal death
what happens if you dont get DNMT2L?
no imprinting - leads to genetic disorders
what does DNMT2?
no one knows - probably does have a function tho
what does hypermethylation of CpG sites lead to?
condensation of chromatin causing transcriptional inactivity
what does histone hyperacetylation and methylation of H3K4 lead to?
transcriptional activity
comment on the DNA methylation present in totipotent cells
tehre will be little to no DNA methylation in totipotent cells
what enzymes start to introduce DNA methylation as cells start to differentiate
DNMT3a and DNMT3b
how does the DNA sequence change from being a pluripotent cell to a unipotent cell?
no change in DNA sequence
- only change in PTM
comment on the mehtylation of CpG islands in pluripotent cells
majority of the islands are unmethylated
in a unipotent cell what is the methylation state of the majority of CpG islands
majority are methylated
is DNA methylation reversable in a specialised cell?
no
what is the only place where you see DNA demethylation?
when the maternal and paternal genome merges you need to remove DNA methylation so that the next generation has a unique DNA methylation signature to give access to the full range of DNA
at what point is the maternal and paternal DNA demethylated?
the paternal DNA is demethylated first at fertalisation
the maternal DNA takes a bit longer but both are completely demethylated by the morula stage
what is being shown here
that the maternal DNA still has some methylation while the paternal DNA is almost completely rid of its methylation
what is genomic imprinting?
deciding whether the maternal or paternal DNA will be the allele expressed to make a certain protein
how many genes are impronted?
around 80 genes
define genomic imprinting
modification of specific genes during gametogenisis so that only tyhe paternal or maternal allele is expressed after fertalisation
does genomic imprinting affect expression and transmission of alleles?
no it only affects expression
- the gene is still transmitted to the offspring
what is the term used to desribe only a single allele out of the 2 being active in the offspring?
functional haploidy
are all genes subject to genomic imprinting?
no just some select few
is Igf2 maternally or paternally expressed?
paternally expressed
what is IGF2
insulin - like growth factor 2
what is H19?
a non-coding RNA
is H19 maternally or paternally expressed?
maternally expressed
what regulates genomic imprinting?
cis-acting Differentially Methylated Region (DMR)
- also known as Imprinting Control Region (ICR)
can you have both IGF2 and H19 expressed in a cell?
no
what are DMR1 and DMR2?
DMR1 is a silencer of H19
DMR2 is an enhancer of IGF2
what does methylation of DMR1 and DMR2 do?
:)
what happens to DMR's to switch on IGF2? and what happens to DMR's to switch H19 off?
DMR is methylated to produce both outcomes
what needs to happen to DMR to switch H19 on and IGF2 off?
needs to be un-methylated
what else is activated to allow maternal H19 to be switched on?
CTCF binds to DMR to prevent methylation
downstream enhancer engement for H19 is activated
what is the outcome in terms of offspring size for activation of the IGF2 and of the H19
activation of IGF2 gives a larger offspring
activation of H19 gives smaller offspring
what is the benifit to the maternal genome to have smaller offspring?
smaller offspring are easier to give birth to
whats the benifit to the paternal genetic line?
having a larger offspring = potentially stronger offspring
how common is prader willi syndrome?
1 in 15,000 live births
what are the symptoms of prader willi syndrome?
what gene is deleted to cause prader willi syndrome
OCA2 gene
what are the symptoms of angelman syndrom?
:)
what causes angelman syndrom?
defective imprinting of mutated UBE2A causing duplication of the paternal genome - means both the maternal and paternal genome are expressed or neither is
what causes X chromosome inactivation in every female?
DNA methylation and histone PTM
summarise the roles of DNA methylaiton
:)
