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

7. Regulation of histone acetylation
in yeast

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.

10. Euchromatin
(De-condensed
heterochromatin Chromatin)
(condensed
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.

12. SWI2/SNF2 ATPase BROMO
subfamily
ATPase SANT
ISWI
subfamily
SWI2/SNF2
ATPase
SUPERFAMILY
ATPase
CHD/Mi2
subfamily CHROMO DNA binding
ATPase ATPase
Ino80
subfamily

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

14. Role In Transcription:
eg. Nucleosome remodeling in
yeast
SWI/SNF
complex
SAGA
complex

16. DHS

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.

22. References
 http://www.nature.com/onc/journal/v20/n24/full/
1204322a.html
 http://highered.mcgrawhill.com/sites/98340923
39/student_view0/chapter10/chromatin_remod
eling.html
 http://www.sabiosciences.com/pathway.php?s
n=Chromatin_Remodeling
 http://www.sigmaaldrich.com/life-science/your-
favorite-gene-search/pathway-
overviews/chromatin-remodeling.html