Flashcards in G7 Deck (32):
how many histone modicfications are possible and why?
280 billion possible modification
each combination of ptm on any number of AA's of tail could cause a specific phenotype
where on a histone is usually modified?
the histone tailprotruding from the nucleosome often serves as a template for epigenetic
what affect could modifications on histones have?
change binding affinities of nucleosome DNA
shift nucleosomes out of the way
change activation of transcription
recruit protein complexes that regulate chromatin state and gene activity
what types of modification can lysine residues go through and what enzymes do this
what type of modifications can serine/thereonin go through and which enzymes does this?
phosphorylation/dephosphorylation by kinase phosphatase enzyme
what type of modications can arginine go through and what enzymes catalyse this?
what is the histone code hypothesis
transcription of genetic info encoded in DNA is in part regulted by chemical modification to hisstone proteins primarily on their unstructured ends.
what is HAT enzyme?
histone acetyl transferase
what does methylation cause at H3K4
= lysine residue methylation
demethylation = silencing
what does methyaltion at H3K9 cause?
silent heterochromatin = silencing
what does acetylation at H3K14 cause
what does methylation (mono/ditri) at H3K27 cause
mono = activation
what does methylation at H3K36 cause
(also lysine residue)
what does methylation at H3K79 and H4K20 cause
signalling G2/M arrest to allow DNA repair.
how can histone modifying enzymes act?
intrinsically (on only single nucleosome) or extrinsically - affect nucleosome:nucleosome int4eractions.
can recruit other proteins to DNA via specific domains.
what does histone modification participate in the regualtion of?
many process; transcription
how can chromatin enzymes be involved in cancer
mutations in enzymes = rubinstein-Taby syndrome and cancer
mutations in chromatin remodelling enzymes can cause cancer
mutations in epigentic effector proteins = rett syndrome cancer
how can the papilloma virus lead to epidermal cacrinomas?
because contains genes that interact with methylation enzymes and histone modifcation enzymes
what can diregualtion of gene expression in cancer cells lead to
- insensitivity to antigrowth signals
evasion of cell death (apoptosis)
impared DNA repair capacity
increased genomic instability
tissue invasion and metastasis (spread of cancer to other parts)
what is knudsons two hit hypothesis of carcinogenesis?
one hit = epigentic, promoter methylation
subsequent events eliminating seconf copy of the gene such as a mutation
what is an example of dergualtion of imprinting leading to cancer
Lol at the IFG2/GH19 locus leads to colon cancer
how can age influence DNA methylation levels ?
Age - tendancy to become hypomethylated with age whereas certain CpG islands become hypermetylated
how can diet influence dna methylation levels
diet - nutrition supplies methyl groups for DNA and histones - methylation via folate and methionine pathways as mammals cant synthesize these things.
how can the environment influence DNA methylation levels
agents such as arsenic and cadmimum
arsenic - causes hypomethylation of ras gene
cadmium - induce global hypomethylation by inactivation DNMT1. associated with cancers
Describe the process by which RB tumour repressor works
H3K9 methylation at promoters in early G1 phase. RB recruits deacetylases and methylases to repress the cyclin E gene
deacetylation and K9 trimethylation of histones results in condensed and transcriptionally repressed chromatin
loss of RB leads to depression of S phase inducing genes and proliferation
what are chromatin remodellers?
large mulitsubunit complexes containing an enzymatic ATPase, core subinits and accessory subunits which load/slide or eject nucleosomes and are involved in cancers
how are chromatin remodelling complexes affected in cancers
hSWI /SNF subunits are deregulated in cancers
what is prader willi syndrome
deregulated genomic imprinting on chromsoome 15
incomplete sexual development
what is angelmans syndrome
loss of paternal genes on chromosome 15 due to imprinting, causes disease by maternal chromosome 15 deletion or inactivation
what is rubinstein taby syndrome
make half the normal amount of CREB gene invovled in growth
broad thumbs and toes
what is rett syndrome
caused by mutations in x chromosome gene involved in epigenetic regulation
effects nearly always females
small hands and feet and decelerated head growth