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Nucleosome Positioning & Transcription Factor Identification

Nucleosome Positioning & Transcription Factor Identification. Zhang Zhizhuo May 2010. Outline. Basic Concept Nucleosome Positioning and Gene Regulation General Transcription Mechanism Genomic Organization of Nucleosomes The Organization of Nucleosomes on Genes Control of DNA Access

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Nucleosome Positioning & Transcription Factor Identification

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  1. Nucleosome Positioning& Transcription Factor Identification Zhang Zhizhuo May 2010

  2. Outline • Basic Concept • Nucleosome Positioning and Gene Regulation • General Transcription Mechanism • Genomic Organization of Nucleosomes • The Organization of Nucleosomes on Genes • Control of DNA Access • Nucleosome Related TF Identification • Enhancer Identification • Integrating Histone Information to Predict TF binding sites

  3. Basic Concept Histone Nucleosome

  4. Basic Concept • Histone • Nucleosome • Linker-DNA • DNA between two nucleosomes • RNA PolyII • An enzyme catalyzes the transcription of DNA • TBP • TATA binding protein and a necessary component of RNA polymerase

  5. ”Bridge” Chromatin remodelling General Transcription Mechanism

  6. General Transcription Mechanism

  7. Genomic Organization of Nucleosomes Deposition of histones on DNA during DNA replication occurs at random positions? Not Really!

  8. Genomic Organization of Nucleosomes  Highly phased or a random continuous distribution

  9. Genomic Organization of Nucleosomes Highly phased or a random continuous distribution Facing inwards or outwards

  10. Distance between Positioned nucleosomes • Tend to be fixed distance • short stretches of linker DNA •  165 bp (18 bp linker) in S. cerevisiae • 175 bp (28 bp linker) in D. melanogaste • 185 bp (38 bp linker) in humans • ISWI complex models the spacing • Linkers might have regulatory functions

  11. The organization of nucleosomes on genes Nucleosome numbering

  12. The organization of nucleosomes on genes Nucleosome numbering H2A.Z levels, acetylation, H3K4 methylation and phasing

  13. Nucleosome Positions Independent positioning Statistical Positioning Analog to Roulette wheel

  14. Nucleosome-Free Region(NFR) Poly(dA:dT) tracts contribute to rigidity We thought promoter regions would be occluded by nucleosomes except when they were activated. But in fact, NFRs demonstrated that open promoter states are stable and common, even at genes that are transcribed so infrequently.

  15. Nucleosome-Free Region(NFR) Low basal levels of leaky transcription might have a general housekeeping function Open architecture of the 5' NFR is necessary for the initial 'pioneering' polymerase or whether transcription itself establishes the NFR from the closed state (after the last transcription)

  16. Transcription start site selection by nucleosomes? Most promoters seem to lack core promoter elements, including a TATA box, the TFIIB recognition element (BRE), INR, downstream promoter element (DPE) or motif ten element (MTE)

  17. Control of DNA Access • DNA accessibility without catalysis • thermal fluctuation • energetically less favourable towards the midpoint of the nucleosome • Binding of one factor might stabilize a partially disassembled state

  18. Control of DNA Access DNA accessibility without catalysis DNA accessibility and remodelling complexes

  19. Control of DNA Access DNA accessibility without catalysis DNA accessibility and remodelling complexes Nucleosome eviction

  20. Nucleosome Related TF Identification Nucleosome dynamics define transcriptional enhancers. Nat Genet 42:343-347. Genome-wide prediction of transcription factor binding sites using an integrated model. Genome Biol11:R7.

  21. Nucleosome Dynamics Define Transcriptional Enhancers Monomethylated H3K4 (H3K4me) : enhancers, Trimethylated H3K4 (H3K4me3) :TSS, Dimethylated H3K4 (H3K4me2) : both the TSS and enhancers

  22. H3K4me2 are destabilized at AR binding site, but better positioning at flanking loci. FOXA1 as pioneer factor to stabilize the nucleosomes.

  23. Motif Analysis in the Paired Nucleosome Regions Identify Nucleosome

  24. Motif Analysis in the Paired Nucleosome Regions Identify Nucleosome Identify Enhancer Region

  25. Motif Analysis in the Paired Nucleosome Regions Identify Nucleosome Identify Enhancer Region Motif Analysis in Enhancer Region

  26. Genome-wide prediction of transcription factor binding sites using an integrated model Eight chromatin marks (H3, H3K4me1, H3K4me2, H3K4me3, H3K9me3, H3K36me3, H3K20me3, and H3K27me3) 

  27. Genome-wide prediction of transcription factor binding sites using an integrated model

  28. Future work Finding candidate nucleosome organizing factors Better understand nucleosome positioning

  29. Reference I) NUCLEOSOME POSITIONING.II) NUCLEOSOME REMODELING. BCH 6415. http://www.med.ufl.edu/biochem/tyang/ http://www.uio.no/studier/emner/matnat/molbio/MBV4230/ Nucleosomedynamics define transcriptional enhancers, Nature genetics 42 (4): 343-7, 2010 Apr Nucleosome positioning and gene regulation: advances through genomics, Nature reviews. Genetics 10 (3): 161-72, 2009 Mar Inducible gene expression: diverse regulatory mechanisms, Nature reviews. Genetics , 2010 Apr 27 Genome-wide prediction of transcription factor binding sites using an integrated model, Genome biology 11 (1): R7, 2010 Jan 22 http://en.wikipedia.org/wiki/Histone

  30. Q&A

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