Presentation chromatin remodelling

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  • 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.
  • SEE PDF for explanation….
  • Presentation chromatin remodelling

    1. 1. CHROMATINRE-MODELLING Presented by: Roll no. 10 : PragyeshDhungel Roll no.21 : Nirjal Mainali Roll no. 34 : Sunil Timilsena
    2. 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. 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. 4. Basic Technique1. Remodeling: change in nucleosome structure, but no change in position2. Sliding: displacing nucleosome along DNA3. Transfer: removing and transferring nucleosome to non-adjacent region of DNA
    5. 5. Two classes of chromatinremodeling enzymes Two classes of enzymes that regulate chromatin structure are:a) Class I : Histone acetylaseb) Class II : Chromatin remodeling factors
    6. 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. 7. Regulation of histone acetylationin yeast
    8. 8. Class II : Chromatin remodelingfactors 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. 9. Chromatin remodelingis 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. 10. Euchromatin (De-condensedheterochromatin Chromatin)(condensedChromatin)
    11. 11. Classifying ChromatinRemodelers 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. 12. SWI2/SNF2 ATPase BROMO subfamily ATPase SANT ISWI subfamily SWI2/SNF2 ATPaseSUPERFAMILY ATPase CHD/Mi2 subfamily CHROMO DNA binding ATPase ATPase Ino80 subfamily
    13. 13. Shared characteristics of chromatin remodelingComplexes : • Bind nucleosomes • Are DNA-dependent ATPases • Recognize histone modifications • ATPase activity can be regulated • Interact with other proteins
    14. 14. Role In Transcription: eg. Nucleosome remodeling in yeastSWI/SNFcomplexSAGAcomplex
    15. 15. DHS
    16. 16. 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
    17. 17. 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 cant recruit histone transferases, instead recruits histone deacetylase to block specialized cell funtions, causing proliferation of cells leading to leukemia.
    18. 18. 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.
    19. 19.  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.
    20. 20.  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.
    21. 21. 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

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