Epigenetics Flashcards
epigenetics
definition
study of changes in gene expression that do not result from changes in DNA sequence
via silencing or activating chromosomal regions
chromatin remodelling/histone rearranging
SWI/SNF = facilitate transcription by repositioning/swiping histones to expose for DBP
ISWI/CHD= inhibit transcription by loading histone on DNA to occlude binding sites
DNA binding proteins
DNA methylation
@cytosines in CG sequences
does NOT affect base pairing
DOES affect methylation-sensitive DNA binding proteins aka prevent transcriptional activators or promote chromatin silencing factors (histones)
methylated regions in genome
either @repetitive DNA or @promoter regions (CpG islands)
-unmethylated in transcribed regions, methylated in silent
hypermethylation
will silence important genes like tumor suppressors
hypomethylation
can activate wrong genes like oncogenes
causes genome instability with retrotransposons bc can make copies of itself and insert into DNA
methylation
establishment and maintenance
established: by writing on unmethylated DNA by DNMT3
-initially on one strand
maintenance and copying: by DNMT1
-copied on second strand
after DNA replication only hemi-methylated again so copied/maintained again
erasing methylation
active demethylation by TET enzymes then base excision
passive demethylation by inhibiting DNMT1 so after DNA replication no maintenance
TET mutations
inc tumor risk
TET requires alpha-ketoglutarate from TCA
histone modifications
acteylation
actetylation of lysine residues in histone tail dec affinity to DNA so opens chromatin and facilitates transcription
activation = activates
histone modifications
methylation
@lysine residues
facilitates binding of regulatory proteins
-activating by H3K4met
-repressing by H5K9met
histone modifications
other
phosphorylation
ubiquitination
writing histone codes
by HATs (acetyl)
activate transcription
or HMTs (methyl)
different reg functions
readers of histone code
methylation sensitive histone binding proteins i.e HP1
activate chromatin modifying enzymes
erasers of histone code
HDACs
repress transcription
metabolism and epigenetics
metabolism gives substrates for chromatin modification
1. acetyl CoA for histone acetylation and NAD+ as cofactor
2. SAM for DNA and histone methylation and alpha-ketoglutarate as cofactor for demethyl
boundary elements
separate heterochromatin from euchromatin i.e HP1
translocation of methylated fragments = silence adj regions
if elements fail > inactivation of adj regions so behaves like a mutation
Rett Syndrome
mutation in methyl-cytosine bindng protein MECP2 gene = lose transcriptional silencing
onset 6-18 mo, autism like, repetitive teeth grinding, hand wringing, motor probs, gait,
-will stabilize after inital deterioration
X linked dominant- affected boys die shortly after birth
imprinting
parent of origin monoallelic expression aka alleles are silenced/imprinted on either mom or dad
explains why phenotype of a mutation varies depending on which parent, and why zygotess with DNA from just one parent are inviable
monoallelic expression
impacts a few genes- can be dependent on parent of origin or random
most genes- bi-allelic expression
parent of origin effect
genes with poo specific imprint normally = balanced amount of protein
-uniparental disomy upsets monoallelic balance
if deletion on pat/maternal homolog abolishes expression of different genes
Prader Willi syndrome
deletion on paternal copy of chromo 15 or maternal uniparently disomy
overgrowth, xs food seeking
angelman syndrome
deletion on maternal copy of chromo 15
autism like features
assoc w/ UBE3A ubiquitin protein ligase
Beckwith-Wiedemann Syndrome
paternal uniparental disomy of chromo 11
overexpress IGF2 = organ problems
microcephaly, macroglossia, umbilical hernia
hypomethylation
cancer
causes instability =
elevated transposon activity
chromo abnormalities
high mutation rate
