Chromosome biology Flashcards
(23 cards)
what percentage of solid tumour cells have aneuploidy?
up to 90%
what are the three levels in the heirachial organisation of interphase chromatin
topologically associating domains (TADs), compartments, chromosome territories
what are TADs?
Topologically associated domains
fundamental units of three-dimensional (3D) nuclear organization
within compartments, big loops of chromatin that contain functional domains.
TADs move between compartments depending if they’re active or inactive
what are compartments?
chromosome territories are divided into compartments that are either silent or active
active is wher transcription is going on
what are the fundamental parts of a chromatin loop in interphase?
and what is their function in the loop?
Cohesin - complex that holds the DNA strands together forming the loop
CTCF - a protein that binds specific DNA sequences (CTCF motifs), which are positioned in the same direction. hence CTCF defines the size of the loop
Loop boundaries - involve cohesin and ctcf only during interphase
In what ways do interphase and mitotic chromatin loops differ?
give three
size of loops
attachment sites
proteins involved in loop formation
how do long distance interactions regulate gene expression
looping of chromatin allows for interactions between distant regions of DNA and regulatory complexes
give 4 ways in which disruption of elements that regulate chromatin organisation contribute/lead to cancerigenesis
- CTCF mutation or abnormal levels
- CTCF/cohesin binding sites are mutated
- breaking down of the TAD border structure (leading to de-regulation of gene expression)
- Pertubation of insulated neighbourhoods’ boundaries
what happens when ctcf binding domins are methylated?
disrupts healthy neighbourhoods and allows other interations that can trigger transcription of genes that are normally silenced
what are insulated neighbourhoods and why are they organised in this way?
Insulated neighborhoods are loops formed by the interaction of CTCF/cohesin-bound anchors containing genes and their regulatory elements
All the loops in insulated neighbourhoods, define domains of similar activity, within the insulated neighbourhood genes are either active or inactive, a way of isolating the domain from other factors
what mutational changes can convert a proto-oncogene to an oncogene
nucleotide substitution (KRAS, EGFR, BRAF)
gene fusion (BCR-ABL)
enhancer hijacking (IgH-MYC)
focal amplification (MYCN, EGFR)
disruption of insulated neighbourhoods
where is the most condensed form of chromatin found?
In mitotic chromsomes
(length up to 10000 shorter than naked state)
what do readers do?
they bind specificallu to modified histones
usually bringing new activity to the vacinity of a modifed histone or alter the structure of the chromatin simply by binding to a histone mark
Some PTMs attract defined ‘readers’ to promote certain outcomes
translation of a histone modification into biological function involves what 4 things
- Writers (enzymes) that are responsible for modifying histones
- Readers (binders) that recognise and interact with modified histones
- Sometimes effectors are needed, usually enzymes that change the status of chromatin to ‘close’ or ‘open’. Some readers may also do this
- Erasers (enzymes) that remove the modification
For the histone code to work properly, all these proteins must be present at appropriate levels
what are the three main epigenetic processes?
- DNA methylation
- Histone modification
- Non coding RNAs
how does misregulated epigenetic control lead to cancer formation?
HDACs responsible for gene silencing and transcriptional repression - can occur in tumour suppressor genes
Histone acetylation at gene promoter and enhancers can promote transcription in oncogenes
Oncohistones are frequently mutated histones that are associated with tumourigenesis (H3K27M pediatric gliomas)
there are tumour promoting and tumour suppressive types of non coding rnas
DNA methylation is associated with resistance
hypermethylation at genes may lead of activation of oncogenes (DLX1)
methylation at promoter can repress tumour suppressor genes (eg P53, BRCA1)
why is the histone code important in cancer biology?
many components of the histone code are mutated in cancer
give some mutations in the histone code that are related to tumour growth
macroH2A
CENP-A/HJURP
ATRX/DAXX
give some mutation in the histone code that lead to invasion or metastasis
H3.3
macroH2A
give two examples of DNMT inhibitors
Decitabine
Hydralazine
give two examples of HDAC inhibitors
valproic acid
suramin
give two examples of HMT inhibitors
TCP
Pinometostat
How can we repair epigenetic components in the treatment of cancer?
By using small drug inhibitors it is possible to restore normal combination of PTMs on histone which may in turn help to get rid of cancer
