Lecture 6 Flashcards
true or false: altered patters of gene expresson is a key feature of cancer
true
the disruption of epigenetic regulatory mechanisms is…. in cancer
prevalent
true or false: we can use altered patters of gene expression to stratify patients
true
aberrant gene expression can be driven by what
specific genomic/epigenomic alterations
different cell types are programmed to express….. set of genes
different
true or fa;se: different cell types are programmed to express different sets og genes but they share the same dn
true
The establishment of different cell
lineages and cell differentiation involves
different gene expression programmes
during….
developmen
The establishment of different cell
lineages and cell differentiation involves
different gene expression programmes
during development, which do not
depend on the DNA sequence itself, but
instead on …… factors.
“epi”-genetic
Epigenetics covers all ….
Epigenetics covers all phenomena that
produces heritable changes in genome
function that do not affect the DNA
sequence
The expressiom state of a gene is determined by what
-the packaging or the accessibility of its dna in the chromatin
-by the presence of transcription factors and chromatin modifying enzymes
accessibility of chromatin to transcriptional regulation is controlled by what?
-modification to the DNA
-modification/rearrangement of nucleosomes
true or false: dna is wrapped in nucleosome
true
what are the 2 subunits in each histone?
-h2a. h2b
-h3 and h4
true or false, the nucleosome has an S terminus
false it has a N terminal tails of the histones protrude out of the nucleosome
what does the pattern of histone modification signify
the status of the chromatin (histone code)
true or false: you can change the N terminal tails
you can’t change the tails post transitionally
The enzymes regulating the post-translational epigenetic modifications on histones have been categorized as…
writers
erasers
readers
movers
what do writers do
-add modifications aka analogous to kinases
-ex: histone lysine methyltransferases (KMTs), and histone
acetyltransferases (HATs)
what do erasers do
-remove post translational modifications aka like phosphatases
ex:Histone lysine demethylases (KDMs) and histone deacetylases
(HDACs)
what do readers do
-are proteins that “read” histone modifications, such as acetylated or methylated residues.
* Bromodomain and chromodomain containing proteins
* Bromodomain recognize the acetylated lysines
* Chromodomain recognize methylated lysines
what di movers do
are chromatin-remodeling proteins that move nucleosomes and allow gene transcription.
histones can be replaced by what
minor variants
what is the role of H3.3
important in transcriptional activation
how do histone variants differ
from the canonical histone by just a few am,ino acid
the minor histone variants are synthesized throughout when
interphase and are often inserted into previoulsy formed cjromatin by a remodeling complex
true ot false: Epigenetic Modifications Annotate Functional
Elements Across the Genome
`
true they annotate non coding elements
what do we use for mapping the epigenome
chip seq
what does the chip seq pull down
the methyl group
what are the active promoters of h3k4
h3k4me2 and me3
what do you use to mapp the genome
atac seq
what does atac seq do
assay for transposase accessible chromatin using sequencinf
Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation via …..
modification to DNA or by modification / rearrangement of nucleosomes (histones).
true or false: global dna methylation patterns vary between different cell types and different stages in devlopment
true
what is the main role of dna methylation
dna silencing
-Genomic imprinting
* Differential expression of maternally and paternally inherited alleles
* X-chromosome inactivation: Compensation for sex differences in gene dosage
* The suppression of retrotransposon elements.
dna methylayion is limited to ….
cytodines and occurs within the contect of the di nucleotide cg
what so dnmt3a and B do
are de novo
methyltransferases that they methylate CG
dinucleotides
* The DNMT1 enzyme maintains existing
DNA methylation patterns
-they are writers
what does tet do
-TET (ten-eleven translocation) enzymes
are methylcytosine dioxygenases (initiate
demethylation
-tis an eraser
true or false: C→T mutations are rare in human DNA.
false: common
what are c to t mutations
- Deamination of cytosine is a very common
reaction in cells and normally produces uracil - Uracil is found in RNA, not DNA.
- Cells are equipped with uracil DNA glycosylase
that removes them as part of the base excision
DNA repair pathway.
Deamination 5-methylcytosine produces….
thymine
DNA methylation is limited to what and occurs when
it is lomited to cytosines and occures within the context of the di nucleotide cg
what are cpg islands
- have a G + C-rich base composition (65% vs 40% for the bulk genome)
- high density of the dinucleotide CpG (5–10-fold higher than the bulk genome)
how long are cpg islands
1kb or less
where are usually cpg islands
50% of them are located close to known transcriptional start sites
-25% are found in main gene body
CGIs associated with transcriptional start sites remain ….. even when the gene is not being transcribed
unmethylated
why are cpg islands importnat
because they represent areas of the genome that have been protected from the mutatong properties of methylation through evolutionary time aka deamination
true or false: dna amination changes are observed in cancer
i dunno but methylation yes
General …..methylation of the
cancer genome
hypomethylation ‘
focal hypermethylation/silencing of tsg promoters, what is there?
CpG island methylator Phenotype (CIMP)
direact mutagenesis of …. containinh sequences of deamination
5mc
Changes in the chromatin structure are dependent of changes ……
in DNA methylation, histone modification and the positioning of nucleosomes
what are oncogenes
dominantly acting cancer genes that resut from an activating mutation in one allele of a cellular proto-concogene
oncugenes are often activated by loss or gain of function
gain of funstion
why are oncogenes over expressed
due to gene amplification
what is epigenic enhancer hijacking
Activated by structural variants that reposition a transcriptionally silenced gene so that it comes under the control of active regulatory elements
what are tumor suppressors
recessive acting cancer genes in which the inativation of both alleles promotes cell proliferation or inhibits apoptosis
-can be mutations, deletions, dna methylation or combination
true or false: a big number of single nucleotide variants are driver mutations
false it is a small number
single nucleotide variants can driver mutations, are they positively or negatively selected
positively because they confer proliferative advantage to cancer cells
name one way to detect cancer driver genes
you look at the genome of those affected vs not and see which is the most mutated
missence vs truncated which is is a driver and a suprssor
-missense: driver
-trunctative: suppresive
IDH1 mutation is sufficient to establish what
the glioma hypermethylator phenotype
IDHD1 is involved in which process
-the TCA
DH1/IDH2 cancer-associated mutations
are specific missense mutations
producing mutant enzymes that convert
2-oxo-glutarate (produced by the normal
allele) to 2-hydroxyglutarate.
what does 2-hydroxyglutarate do
2-hydroxyglutarate inhibits multiple
enzymes that depend on 2-oxoglutarate
as a cofactor and work in epigenetic
modification, including certain DNA
demethylases, such as TET2, and various
histone demethylases. That can cause
reprogramming of the cell to make it less
differentiated
what are copy number variants useful for
to detect cancer, more copy number variants= cancer
if there is a gain of copy in someone that has a tumor what does it mean and deletions too
-more cpoies= oncogene
-less copies= supressor
true or false: tumor genome is not the same as the reference genome
true
* Copy number gains can be
incorporated into the Genome
(ie. Tandem duplications)
* However, many high-level
amplifications occur on circular
extrachromosomal DNA
(ecDNA)
what does circular ecdna promote
accessible chromatin and high oncogene expression
true or false: half of human cancer mutations harbor mutations in chromatin related proteins
true
what do malignat cells exhibit
- Genome-wide alterations in DNA
methylation - Chromatin structure
- Regulatory element activity
- Deranged developmental programs
- a differentiation block or epigenetic reprogramming
driver mutations in h3.3 and chromatin remodeling genes are in which canver
paediatric glioblastoma
what is chondroblastoma and giant cell tumor og bone have for mutatins
h3f3a and h3f3b mutation
Mutations in histone H3.3 (encoded by H3F3A or H3F3B) commonly occur at three residues: ….
K27, K36 and G34.
H3.3-K27M and H3.3-K36M mutations are dominant …… and reduce the genome-wide ……. of H3K27 and H3K36, respectively
H3.3-K27M and H3.3-K36M mutations are dominant negative and reduce the genome-wide methylation of H3K27 and H3K36, respectively
H3.3-G34R and H3.3-G34V mutations reduce the levels of ….. on the same or nearby nucleosomes
H3K36me3
The …… chromatin Remodeling Complex
is altered across many cancer types
h* >20% of all cancers harbour mutations in
SWI/SNF-encoding genes
how many genes encoding for the swi/snf family are mutated in cancer
9
Mutations in specific SWI/SNF genes are enriched in particular cancer types, which suggests …….
-differential roles for individual components
-The tumour-suppressor activity is most likely attributable to their roles in facilitating transcription factor function, which is central to cell-fate differentiation.
true or false: chromatin remodelers are multi subunit complexes
true
what do chromatin remodelers use
use the energy from atp hydrolysis to reposition, eject, slide ot alter the composition of nucleosome
what do chromatin remodelers do
allow access to dna binding proteins and the transcriptional machinery to dna in order to facilitate gene expression
true or false:swi/snf and pcr complex help eachother
nah they probs fuck eachother up
Noncoding mutations in regulatory elements can lead to …..
the aberrant expression of oncogenes, transcription
factors and chromatin regulators resulting in aberrant gene expression
true or false: non coding regulatory elements harbor a larger fraction of somatic mutations
true
is tert coding or non coding
non coding
involved in mutations in human melanoma, glioblastoma, oligodendroglioma
recurrent non coding u1 snrna mutations drive what
cryptic splicing in shh medulloblastoma
true or false: Noncoding enhancers outside of oncogenes ( ie. MYC, MYCN, AR,
KLF5, and EGFR) are always selectively amplified with their respective oncogenes
false it is with or eithout
with: myc, mycn
without myc too often just duplicated
what can enhancer hijacking events explain
aberrant gene expression patterms
true or false: tads interact with eachother
false they interact with themselves but not eachother
explain chromatin 3d thing
idsabfyrgaofao
enhancer hijacking activated wich family in oncogenes in meduloblastoma
GFI1
can you duplicate an enhancer in cancer
yeah especially in tads, you can delete,
…… Duplication is highly recurrent in Group 4 Medulloblastoma
SNCAIP
true or false, enhanver hijacking events are common
true
what does ecdna do
enables distal dna interactions
