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SUMMARY:Higher order from high disorder: DNA condensation by linker histon
 e tails - Katherine Stott (Department of Biochemistry)
DTSTART:20200129T103000Z
DTEND:20200129T113000Z
UID:TALK138856@talks.cam.ac.uk
CONTACT:Catherine Xu
DESCRIPTION:Disordered proteins play an essential role in a wide variety 
 of biological processes. One such protein is Histone H1\, which condenses
  chromatin – the complex of genomic DNA and its packaging proteins – 
 in a way that is still poorly understood\, despite decades of research. W
 hile the textbooks tell us that the endpoint of this condensation proces
 s is a 30 nm fibre\, the fibre is elusive in vivo. Instead\, the latest
  super-resolution methods reveal a heterogeneous\, dynamic and liquid-l
 ike assembly\, and the growing evidence\, from us and others\, points to 
 liquid-liquid phase separation as a mechanism that could produce a compa
 ct but dynamic ‘ground state’ of H1-bound chromatin. The hypothesis 
 is compelling\, since a liquid condensate is a more plausible means by w
 hich chromatin could respond quickly to environmental stimuli.\n\nThe reg
 ion of H1 that is responsible for chromatin condensation is its long\, hi
 ghly disordered C-terminal tail. However\, the tail is all but invisible 
 in the best cryo-EM structures of chromatin to date\, implying some degr
 ee of disorder remains. We have developed a model system that is amenable
  to NMR and other biophysical techniques. The model allows us to study t
 he nature of this disordered state at high resolution. In addition\, it r
 ecapitulates the condensing behaviour of chromatin\, forming phase-separ
 ated liquid condensates\, while allowing capture of the thermodynamics un
 derpinning the various processes. Before condensation\, we find the prot
 ein\, despite its high affinity for DNA\, does not undergo a disorder-to-o
 rder transition on binding\, but forms a ‘fuzzy complex’. We can also
  use the model to study the phase-separated state\, which under certain 
 conditions contains higher-order structure. The condensate is also highly
  sensitive to the phosphorylation state of the protein. These ‘bottom-
 up’ findings are broadly consistent with the current in vivo picture.
  They also provide insights into how tight binding need not be driven by
  disorder-to-order transitions\, and how condensation and higher-order str
 ucturing can be dynamic and thus exquisitely sensitive to perturbation b
 y post-translational modifications\, broadening the repertoire of mechani
 sms that might regulate chromatin and presumably other macromolecular ass
 emblies.\n\nTurner AL\, Watson M\, Wilkins OG\, Cato L\, Travers A\, Thom
 as JO\, Stott K. “Highly disordered histone H1-DNA model complexes and
  their condensates.” Proc Natl Acad Sci U S A. (2018) doi: 10.1073/pn
 as.1805943115.\nAssociated commentary: https://doi.org/10.1073/pnas.18169
 36115
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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