Chromatin organization and loop extrusion

6 problems

• Is chromatin in the nucleus a liquid, a gel or a solid?

  Contested

  Experiments disagree on whether chromatin flows like a thick liquid or holds its shape like a soft solid at scales below a micrometer. The answer decides how genes move and how mechanical forces reach the genome.

• What physical interactions create A and B compartments?

  Open

  Active and inactive parts of the genome separate into two spatial groups, somewhat as oil separates from water. Which molecular interactions cause this, and how it competes with loop extrusion, is not settled.

• How enhancer-promoter contact frequency sets transcription

  Open

  Genes are often switched on by DNA control elements called enhancers located far along the chain, which must come close to the gene. How the frequency of such contacts translates into gene activity is unknown.

• Speed and lifetime of loop extrusion inside living cells

  Partially resolved

  Purified cohesin extrudes DNA in a test tube at roughly a thousand base pairs per second. How fast it works inside a crowded nucleus, and how long loops last, has been measured at only a few sites.

• Does loop extrusion alone build and stiffen mitotic chromosomes?

  Partially resolved

  Before division, each long chromosome is packed within minutes into a compact rod. Motors called condensins form loops around a helical axis, and whether loop formation alone explains the rod's shape, stiffness and the separation of the two copies is not settled.

• Stepping mechanism of SMC loop-extruding motors

  Partially resolved

  Cohesin and condensin are ring-shaped protein machines that pull DNA into loops by burning ATP. Single-molecule experiments show steps of hundreds of base pairs, comparable to the size of the protein, and how the structure achieves this is unknown.