A Genomic Code for Nucleosome Positioning

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A Genomic Code for Nucleosome Positioning
Authors Segal E., Fondufe-Mittendorfe Y., Chen
L., Thastrom A., Field Y., Moore I. K., Wang
J.-P. Z., Widom J.
Presented by Apostol Gramada
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DNA organization Chromatin
Taken from http//sgi.bls.umkc.edu/waterborg/chro
mat/chroma09.html
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Nucleosome organization
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Nucleosome organization

• An octamer of 8 histone chains, 2 of each of the
  following H2A, H2B, H3, H4.

• H3, H4 highly conserved in eukaryots.
• 147 bp per nucleosome
• DNA sharply bent and tightly wrapped in approx
  1.7 turns around the histone core.
• DNA bends discontinuously with the periodicity
  of the helical repeat.
• Bending is facilitated by certain dinucleotides
  placed at the right positions.

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Nucleosome organization

• DNA in nucleosomes is far more sharply bent than
  in unstressed naked DNA gt significant free
  energy cost needed for stability.
• Particular DNA sequence could reduce this cost
  by
• either having an inherent bendedness
• being more easily bendable (more flexible).
• The later seems to be more supported by
  evidence.
• The 10 bp periodicity of AA/TT, TA, GC seems to
  be an especially flexible sequence motif.

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Nucleosome positioning

• DNA sequences differ in their ability to bend
  sharply. This affects the DNA binding affinity of
  the histone octamer.
• In vitro studies show a wide range of affinities
  with respect to sequence variability (approx
  1000-fold). Some sequences highly preferred.
• Is this mechanism used to control the access to
  specific binding sites?
• The positions of the nucleosomes may have
  important inhibitory or facilitatory roles in
  regulating gene expression.

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Nucleosome positioning current views

• Sequence preferences is over-ridden by
  nucleosome remodeling complexes which move them
  to new locations whenever needed.
• Opposing view the remodeling complexes only
  enable the nucleosomes to sample rapidly
  alternative positions and therefore compete
  efficiently with DNA binding proteins. They do
  not determine their destination however. Then,
  the genome would encode a nucleosome organization
  intrinsic to the DNA sequence alone, comprising
  sequences with both regions of low and high
  affinity for nucleosomes.
• The high affinity regions will be occupied in
  vivo and the detailed distribution of nucleosome
  positions will significantly influence the
  chromosome functions genome-wide.

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Validating a nucleosome-DNA interaction model

• The data 199 mono-nucleosome DNA sequences
  (142-152 bp) from yeast.
• Used to construct a probabilistic model
  measuring the sequence preferences of yeast
  nucleosome
• Generate distribution functions at each site on
  the nucleosome for all dinucloetides, from the
  population of the 199 sequences.
• A probability can then be assigned to each
  sequence of 147 bp.
• Derive a thermodynamic model for predicting the
  nucleosome positions genome-wide from all legal
  configurations of nucleosomes (no overlap, at
  least 10 bp away).

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Validating a nucleosome-DNA interaction model
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Validating a nucleosome-DNA interaction model
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Validating a nucleosome-DNA interaction model
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Validating a nucleosome-DNA interaction model
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Validating a nucleosome-DNA interaction model
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Predicting nucleosome organization in genomic DNA
sequence
Resulting intrinsic nucleosome organizations
mutually exclusive organization dominate, a
single organization dominate, none dominates gt
may reveal potential regulatory role of
nucleosomes.
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Predicted nucleosome organization reflects in
vivo data

• Orange Data in vivo.
• 54 within 35 bp (only 39 by chance).

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Predicted nucleosome organization reflects in
vivo data

• Comparison to three genome-wide measurements
  reveals
• significant correspondence between predicted and
  experimental nucleosome-depleted coding and
  intergenic regions 68 of 57 depleted coding
  regions and 76 of 294 depleted intergenic
  regions.
• strong correspondence with a higher resolution
  nucleosome map 45 within 35bp distance (32 by
  chance).

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Predicted nucleosome organization reflects in
vivo data

• Compared prediction of yeast model with one
  using only nucleosome-bound sequence from chicken

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Predicted nucleosome organization reflects in
vivo data
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Global features of intrinsic nucleosome
organization in yeast

• From 11 mil positions gt 15800 stable ncls.
  gt cover 20 of genome. ? array?
• Fig d shows the distribution of pairwise
  distances between stable ncls. gt periodicity of
  177 bp extending over six positions ? higher
  level chromatin organization?

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Nucleosome organization varies by type of genomic
region

• Centromer function requires enhanced stability
  gt max occupancy
• Highly expressed Ribosomal RNA and transfer RNA
  gt low predicted occupancy
• Genes that very their expression levels
  (Ribosomal protein) in different conditions
  requires other mechanisms.

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Nucleosomes facilitate their own remodeling

• Analyzing 1900 genes from a gene annotation
  database and various studies shows significance
  association with either high or low predicted
  occupancy
• In particular, the chromatin remodeling complex
  RSC is associated with low occupancy gt genomes
  facilitate their own remodeling

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Low nucleosome occupancy encoded at functional
binding sites

• Stable ncls. over non-functional sites gt
  decrease accessibility to transcription factors.
• Tests showed for 37 (out of 46) occupancy was
  lower over functional sites than for
  non-functional sites.

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Low nucleosome occupancy encoded at transcription
start sites
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Conclusions

• Nucleosome organization is encoded in eukaryotic
  genome
• The limited predictive power (50 of in vivo
  nucleosome organization) is explained by a too
  crude model yet
• a more accurate nucleosome-DNA interaction model
• no account for favorable interactions and for
  steric hindrances implied by the 3D ncls
  structure
• no account for competition with binding proteins.

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Math
WcS statistical weight of sequence S with
nucleosome configuration c.
Legal nucleosome configuration
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Math