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Presentation chromatin remodelling
1. CHROMATIN
RE-MODELLING
Presented by:
Roll no. 10 : PragyeshDhungel
Roll no.21 : Nirjal Mainali
Roll no. 34 : Sunil Timilsena
2. Introduction
Gene Expression in Eukaryotes may include
Chromatin Remodelling as part of
transcriptional activation.
Chromatin remodeling is the enzyme-assisted
movement of nucleosomes on DNA.
3. Basic subunit of chromatin.
i.e Nucleosome
Eukaryotic DNA is tightly packaged into repeated
structures known as nucleosomes.
Individual nucleosomes consist of histone
octamers with 146 (or 147) base pairs of double-
helix DNA wrapped around it.
Histone Protein can physically block interaction
between Promoter DNA sequences and protein
needed to initiate transcription.
Chromatin rearrangement modifies the Histone-
DNA structure so that transcription can occur.
4. Basic Technique
1. Remodeling: change in nucleosome
structure, but no change in position
2. Sliding: displacing nucleosome along DNA
3. Transfer: removing and transferring
nucleosome to non-adjacent region of DNA
5. Two classes of chromatin
remodeling enzymes
Two classes of enzymes that
regulate chromatin structure are:
a) Class I : Histone acetylase
b) Class II : Chromatin remodeling factors
6. Class I : Histone acetylase
Don’t alter nucleosome position
Covalent modification of histone proteins.
Includes histone tail modifications
(Ac, Me, P, Ub, etc.)
Proteins recruited by these modifications
include: i)transcription factors
ii)ATP-dependent nucleosomal remodeling
enzymes
iii)histone modifying enzymes
8. Class II : Chromatin remodeling
factors
It shifts nucleosome position with respect to
DNA, exposing regulatory sequences.
These are often refered to as Swi/Snf factors
because they were first identified as yeast
mutants defective in mating type switching and
in the ability to metabolize sucrose (sucrose
non-fermenting).
9. Chromatin remodeling
is an active process
Chromatin remodeling factors use energy from
ATP hydrolysis to rearrange the packing of
nucleosomes in higher order chromatin structures.
Remodeling improves access to DNA or histone
binding sites recognized by transcriptional
regulators or histone modifiers.
Some of these bind to :
i) Activation domains and de-condense the
associated chromatin.
ii) Repression domains and condense the
associated chromatin.
11. Classifying Chromatin
Remodelers
Chromatin remodeling complexes are
classified based on protein motifs found in
addition to the ATPase domain, or on how the
ATPase domain itself is structured.
This classification is purely
structural, designed to make it easier for us
humans to sort them all out – it may not accord
with functional criteria.
13. Shared characteristics of chromatin remodeling
Complexes :
• Bind nucleosomes
• Are DNA-dependent ATPases
• Recognize histone modifications
• ATPase activity can be regulated
• Interact with other proteins
17. Chromatin and cancer:
Cancer can occur when essential regulatory
proteins are altered such that development
stops but the cells can still divide.
Examples: avian Erythroblast virus changing
normal functional properties of thyroid
hormone receptor(TR) by introducing
oncoprotein v-ErbA.
Acute myeloid leukemia(AML) and
Promyelocytic leukemia(PML) in humans
18. Oncoprotein v-ErbA:
TR directs differentiation of chicken blood cells
by binding to thyroid hormone, through
targeting of chromatin remodeling machinery
including histone transferases.
but v-ErbA, cant bind to thyroid hormone, so
can't recruit histone transferases,
instead recruits histone deacetylase to block
specialized cell funtions,
causing proliferation of cells leading to
leukemia.
19. AML and PML:
associated with chromosomal translocations.
In AML, gene that is disrupted encodes a
transcription factor AML-1, which controls
myeloid specific gene expression.
in chromosomal translocation, DNA binding
domain of AML-1 binds with a protein
ETO, that interacts with a histone
deacetylase, that leads to repression of cell
differentiation and leads to leukemia.
20. Similarly in PML, retonic acid receptor(RAR)
(recruits histone deacetylase) binds to PML
and leads to to failure of myelocytes to
differentiate and results leukemia.
PML-RAR can bind with trans-retonoic acid
which leads to conformational change to PML-
RAR and release of histone deacetylase.
This leads to remission of leukemia.
21. in cell cycle controlling pathways also mutated
genes like
cyclin dependent kinase inhibitors(p16) and
retinoblastoma(Rb)
cause cancer.
but if recognition and selective inhibition of
these chromatin remodelling
pathways can be done then cancer can be
cured.
thus this area has a wide scope in therapeutic
and pharmaceutical industry.
Why do you need ATP to move nucleosomes around??????1.Bending DNA around a bunch of histones depends on DNA sequence to some extent .Some sequences bend more easily than others2. Nucleosomesdo have strong affinity for DNA and even have sequence preferencesThis preference may be exploited in nature to organize a chromatin landscape energetically conducive (or not) to gene expression.3.But that landscape must change as gene expression requirements change……and this requires energy.