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High-resolution mapping and analysis of the human regulatory genome

High-resolution mapping and analysis of the human regulatory genome. John Stamatoyannopoulos , M.D. Depts. of Genome Sciences & Medicine University of Washington. Genes, regulatory DNA, and epigenetic features. Genes, regulatory DNA, and epigenetic features. promoters enhancers

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High-resolution mapping and analysis of the human regulatory genome

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  1. High-resolution mapping and analysis of the human regulatory genome John Stamatoyannopoulos, M.D. Depts. of Genome Sciences & Medicine University of Washington

  2. Genes, regulatory DNA, and epigenetic features

  3. Genes, regulatory DNA, and epigenetic features • promoters • enhancers • - silencers • insulators • etc.

  4. Overview Part I: Mapping the human cis-regulatory landscape Part II: Footprinting the human genome

  5. Genes, regulatory DNA, and epigenetic features DNaseI • promoters • enhancers • - silencers • insulators • etc.

  6. DNaseI hypersensitive sites mark regulatory DNA Promoters DNaseI Hypersensitive site (DHS) Enhancers ~100,000 – 250,000 DHSs per cell type (0.5-1.5% of genome) genome.ucsc.eduwww.epigenomebrowser.org

  7. Mapping the human cis-regulatory landscape

  8. Deep maps of human regulatory DNA

  9. Creating publicly available atlases of human regulatory DNA genome.ucsc.eduwww.roadmapepigenomics.org

  10. Cell type- and lineage-selectivity of regulatory DNA

  11. Distribution of DHSs relative to genes and transcripts

  12. A global atlas of human regulatory DNA – overview • >250 cell types, tissues, and developmental stages • Model cell lines, Primary cells in culture • Ex vivo hematopoietic cells, Fetal tissues (late 1st – late 2nd trimester) • ~100,000 - >250,000 DHSs per cell type (0.5-1.5% of genome) • Collectively >3 million distinct elements • ~800,000 cell type-specific, ~3,500 constitutive • Comprehensive annotation of known regulatory DNA • 99% of experimentally-validated enhancers, silencers, • insulators, locus control regions

  13. DNaseI accessibility parallels cumulative transcription factor occupancy

  14. DHSs reflect the cumulative action of transcription factor binding

  15. DHSs reflect the cumulative action of transcription factor binding

  16. DHSs reflect the cumulative action of transcription factor binding

  17. DHSs mark a rich regulatory landscape Regulatory effects of CpG methylation De novo promoter identification Cell-selective regulatory selection

  18. Footprinting the Human Genome

  19. DNaseI hypersensitive sites mark regulatory DNA DNaseI Hypersensitive site (DHS)

  20. Genome-scale mapping of transcription factor footprints

  21. Genome-scale mapping of transcription factor footprints

  22. Genome-scale mapping of transcription factor footprints

  23. Genome-scale mapping of transcription factor footprints

  24. Genome-scale mapping of transcription factor footprints

  25. Genome-scale mapping of transcription factor footprints

  26. Visualizing cell-selective and allelic regulation

  27. Visualizing cell-selective gene regulation

  28. Visualizing allele-specific occupancy

  29. A direct and quantitative measure of TF occupancy

  30. Footprinting is a quantitative measure of in vivo factor occupancy

  31. Footprinting is a quantitative measure of in vivo factor occupancy

  32. TF structure is imprinted on the human genome

  33. TFs show distinct, stereotyped DNaseI cleavage patterns NF1 ~10,000 motif instances in DHSs (unsorted)

  34. DNaseI cleavage patterns parallel TF structure

  35. DNaseI cleavage patterns parallel TF structure

  36. DNaseI cleavage patterns parallel TF structure

  37. TF structure is imprinted on the human genome

  38. The footprint of transcription initiation

  39. The footprint of transcription initiation

  40. The footprint of transcription initiation

  41. The footprint of transcription initiation +1

  42. TF recognition sequences within the footprinted initiation zone Motifs within footprint

  43. The footprint of transcription initiation +1

  44. The footprint of transcription initiation +1 Buratowski et al. Cell, 1989

  45. An expansive cis-regulatory lexicon encoded in TF footprints

  46. Deriving the human regulatory lexicon de novo

  47. Deriving the human regulatory lexicon de novo

  48. Deriving the human regulatory lexicon de novo

  49. Novel motifs are functionally conserved in mouse

  50. Novel motifs are under selection in human populations

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