Chromosomes Flashcards
What is each chromosome made of?
1 linear strand of DNA
When is DNA most tightly packed?
When cells are dividing
What is a karyotype?
No., size & shape of chromosomes in the nucleus
What is different about the chromosomes in Klinefelter’s syndrome?
XXY
What is a nucleosome?
How many times is the DNA wound per histone?
How many base pairs are wrapped around a histone?
Length of DNA coiled around a core of histones
1.67
147
What are the 4 core histones?
What do 2 pairs of tetramers form when bound together?
H2A
H2B
H3
H4
An octamer
What is a nucleosome made up of?
2 core histones
Linker DNA
H1 (a histone)
How are nucleosomes dynamic?
- Chromatin remodelling factors slide along DNA
- Exchange histone octamers or subunits
- Remove core histones
- -> alters structure
What is special about the histone tails that stick out?
They can be modified by chemical groups
e.g. 1-3 methyl groups, acetyl groups, phosphate groups
Where are histone tails mostly methylated?
Lysines
- up to 3 methyl groups can be added to 1 lysine
What happens to the chromatin when histone tails are methylated?
How does this affect gene expression?
Chromatin condenses
Genes repressed
What happens to the chromatin when histone tails are acetylated?
How does this affect gene expression?
Chromatin de-condenses
- histones move further apart
Genes expressed
How is heterochromatin self-propagating?
Chromatin modifications can spread along chromosomes
- methylated histones recruit more histone methylases
What is the ‘position effect’?
A normally active gene is silenced because of proximity to heterochromatin after DNA breakage & re-joining
(translocation events)
What are the other types of histone modifications?
> serine phosphorylation
Ubiquitination
SUMOlyation
What are the 4 types of regulatory proteins that bind to marked proteins to read the ‘histone code’?
> chromatin remodelling complexes
transcription activators
transcription repressors
DNA damage repair complexes (H2A.X)
What are epigenetics?
Who can they be passed between?
The study of heritable phenotype changes w/ no change in DNA sequence
> parent to offspring via germ cells
mother to daughter cells
What can cause epigenetic imprints?
> Exposure to pollutants
Stress
Drugs
Famine?
How can epigenetics lead to cancer?
Tumour suppressors hypermethylated
= silencer turned off
–> excessive cell division
Describe DNA methylation in epigenetics
Adding methyl groups to DNA (CpG sites)
= represses gene transcription
Give examples of when DNA methylation is essential for normal development
What is DNA methylation affected by?
> embryonic stem cells are largely de-methylated (pluripotent cells don’t require a lot of silencing)
methylation in cell differentiation
- diet
- environment
- ageing
What are the functional links between histone & DNA methylation?
> Gene silencing
Histone lysine methylation DNA methylation
Histone 3??
Maintenance methylation
What is maintenance methylation?
Maintaining methylation patterns on newly-synthesised DNA strands after replication
e.g. for a liver cell to remain as a liver cell it must inherit epigenetic marks
Describe the higher-order chromatin packing
30nm fibre of nucleosomes are assembled into loops on protein scaffold
–> form coils of heterochromatin
What are the 2 examples of territories within the nucleus that represent the spatial arrangement of chromatin?
LADs = Lamina-associated domains
TADs = Topologically associated domains
What are TADs formed by?
Cohesin
= ring-shaped protein complex that physically bundles chromatin
What are TAD boundaries formed by?
CTCF
(=CCTC-binding factor)
= a transcription factor expressed in all cell types
What are insulated neighbourhoods?
What happens in these regions?
Chromosomal loop structures formed by the physical interaction of 2 DNA loci bound by CTCF and co-occupied by cohesin
There is co-regulation of genes
What are the 2 types of heterochromatin?
Facultative
Constitutive
Describe facultative heterochromatin
= Parts of genome are silenced but have the potential to be expressed
> may switch between hetero- & euchromatin states
modification of histones or DNA
Describe constitutive heterochromatin
= remains condensed throughout cell cycle
> highly repetitive sequences
may play role in chromatin structures
telomeres & centromeres
What are telomeres?
Long repetitive sequences that protect the ends of chromosomes
- TTAGGG x 2,500 in humans
11 kb at birth –> 4 kb in old age
Why do telomeres get shorter?
DNA replication enzymes cannot replicate v ends of DNA strands
- lose some telomeres w/ every cell division
What is the ‘hayflick limit’?
no. of times a human cell population will divide before cell division stops
When don’t telomeres get shorter?
Why?
If the cells express telomerase
e.g. germ cells, embryonic stem cells & cancer cells
They add telomere repeat sequences to the end of telomeres
What is a centromere?
A specialised DNA sequence of a chromosome that links a pair of sister chromatids
= junction of replicated chromosomes
What is the centromere the site of?
Where microtubules attach during mitosis
- at the kinetochore
What can centromere instability result in?
Mis-segregation of chromosomes
–> embryonic death & cancer malignancy
How is chromosome replication initiated?
Multiple origins on each chromosome
- each origin fires once per cell cycle
= ensures that DNA is copied only once
How is chromosome replication timed?
Euchromatin replicated early
Heterochromatin replicated later
What are the different changes in chromosome structure called?
> deletion > duplication > inversion - paracentric - pericentric > translocation - balanced - unbalanced > dicentric chromosome
Give an example of fragile regions for chromosomal breaks
TAD boundaries
What are the 2 types of leukaemia?
ALL = acute lymphoblastic leukaemia AML = acute myeloid leukaemia
How is leukaemia caused?
1.translocation between chromosome 9 & 22
2. fusion of 2 genes:
> BCR = S/T kinase + Rho GEF
> ABL1 = NES + NLS
3. = BCR-ABL fusion protein
What does the BCR-ABL protein do?
Constitutively activate kinase (= always on) = oncogene --> over-proliferation =stem-like state = resistance to cell death
Which chromosome changes have occurred in human evolution?
Telomere-to-telomere fusion in chromosome 2
(all other primates have 2 chromosomes where we have chromosome 2)
Duplication of SRGAP@
–> changes in neurons
= sensory perception, memory & language
