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
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
- basic polymer linked monomers
- add model features to test.
- arrays of loops
- 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.
- 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?
- 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
This entry was posted in Seminars
. Bookmark the permalink