Geoff Fudenberg Thesis Defense

Thesis Defense in Biophysics 05/13/15


  • many different text book picutres of mitotic chromosome
    • middle scale: rosettes? spirals of spirals? Accordion coils?
  • many functional characterizations of the 1D genome sequence
  • Hi-C method explained.
    • had to develop appropriate normalization pipeline
    • now have maps for many species


  • human contact maps (2009) — 100 fold difference in lengths, see scaling exponent ~1 across this range.
    • conclusion chromosomes are polymers
    • two compartments.
    • year 1 of Geoff’s PhD
  • TADs

cycle dependent differences

  • metaphase more gentle slope (longer range contacts)
  • more homogeneous
  • (3 cell types examined)
  • locus specific organization lost in metaphase
  • cell type specific contacts (there certainly are some) are largely lost
    • not evident in the contact range map, but didn’t expect that.
  • distinguish between hierarchical models (e.g. coils of coils). and loop array models for metazoan chromosmes

Polymer models

  • basic polymer linked monomers
  • add model features to test.
    • arrays of loops
    • confinement
    • locus specific interactions
  • loops of loops model (hierarchical distinguishable fiber — contact probability vs. distance decays rapidly (more so than observed in metaphase)
  • can find scaffold maps that produce this, IF positions of loops are variable from cell-to-cell.
  • loops not formed by dimerization. Formed by linking consecutive marks
    • random looping model not consistent with HiC data
  • Cohesin complexes have the ability to form loops and extrude the DNA through the cohesin loop.
    • see citations.
    • Q: Comment more what is known about the mechanism of loop extrusion.
  • add multiAT hook protein to xenopus chromatin and this condenses into a long shape.

Interphase organization

  • compartments vs. domains
    • domains are linked to regulation (guide regulatory elements to genes)
    • domains inhibit contacts across domains
    • Hi resolution Hi-C loops/peaks-at-corners diversity in domain structure + complex domains / loops within loops
  • could loop extrusion and boundaries to loop extrusion give rise to interphase domain organization?
  • Model
    • factors can bind, exchange with solvent, pump DNA
    • location bound is stochastic (?) — would it be averaged out across cells. ??
  • model results
    • can give rise to complex domains,
    • can you walk us through the intuition / loop combinations that give rise to one of these complex domains?
    • does multiloop / loops-within loops require
  • boundary deletion and spreading (cite Nora 2012) – re-examine this.
  • loop extrusion more like to care about direction of sites (in-pointing CTCF cites).


  • boundaries block extrusion at certain points along chromsome.
  • allow nested loops. (loops stacked completely together).
  • Kleckner — what if loops tend to form by collision, in a way limited by persistence length of fiber.
  • extrusion is an interesting explanation for how a 1D boundary becomes a 3D boundary.
    • well, really all this gives you in nearest boundary element finding.
    • not sure this works. Internal interaction within a domain?
  • is extrusion
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