Chromatin dynamics

Keywords: chromatin dynamics, Institut Curie, regulation of DNA, research

Read the scientific activity report. (pdf 5Mo, last update 3th, february 2010)

Chromatin organisation in the nucleus is important both for the compaction of DNA into the nucleus and for the control of many genome functions including DNA transcription, replication, repair and recombination. This ‘packaging' of the genome provides a large repertoire of information in addition to that encoded genetically. This layer of so-called ‘epigenetic' information is stable and can be inherited through cell division, even though it is not encoded genetically.

One way in which epigenetic information can be conveyed within chromatin is by post-translational modification of histones, the major protein components of chromatin. According to the ‘histone code hypothesis' these post-translational marks can be read by the cell and thus used to define active, repressed or inert chromatin states. Each cell type is thought to display a specific 'epigenome‘.

Our team is interested in understanding how both genetic and epigenetic information is established, propagated, and maintained, as well as how it may change during development and in response to environmental cues. Potential errors can lead to misregulation of genome functions, which may have implications for various diseases, including cancer. We hope, therefore, that our research will contribute not only to a better understanding of nuclear organisation during the normal life of the cell but also to understanding pathological conditions such as cancer and, ultimately, to treating cancer.

Fig. 1 

Our general objective has been to dissect the mechanisms of chromatin assembly, from the basic structural unit, the nucleosome, up to higher-order structures in the nucleus (Fig. 1).

Over the past few years (2003-2006) we have focused on the roles of histone chaperones. Because histones are very basic proteins, they tend to interact non-specifically with more acidic proteins and with nucleic acids; these chaperone proteins help to transfer histones from one site to another, for example, to load histones onto DNA during chromatin assembly. Also, a constantly controlled flow of histones enables the cell to adapt to physiological demands during the cell cycle and development as well as in response to DNA damage.

Fig. 2 

We have characterised several key chaperones involved in nucleosome assembly: CAF-1, HIRA, ASF1a and ASF1b. We identified CAF-1 as a marker of cell proliferation in breast cancer. We also found these chaperones to be part of multiprotein complexes in vivo, with different specificities for individual histone H3 variants (Figure 2).

We were able to define the dynamics of new histone incorporation during repair of UV damage in chromatin. Interestingly, specific modifications can be found on histones even before their incorporation into chromatin. Taken together, our findings have thrown light on the fundamental issues of the dynamics, fate and inheritance of histones together with their specific marks typical of particular chromatin domains. A current challenge is to understand how the maintenance and duplication of both genetic and epigenetic information is ensured and co-ordinated. Our working hypothesis is that histone chaperones function in an ‘assembly line', and that their specificity for individual histone variants contributes to the specific marking of defined regions of the genome.

Fig. 3 

Our plan is to analyse the regulatory pathways that target histone chaperones to control the assembly line and its connecting network. Our specific approach is based on tools and model systems that combine biochemistry, to study complexes at a molecular level, and cell biology, to integrate them in vivo and examine specific nuclear domains (e.g. centromeric heterochromatin; Fig. 3).

Our developmental studies will favour Xenopus as a model organism in which we can validate the relevance of our findings from experiments in vitro and, ultimately, develop medical applications.

Our team is a co-ordinating member of the Epigenome Network of Excellence: the focal point for the European epigenetics research community, and member of the Research Training Network working on checkpoints, the DNA damage response and cancer.

Last update: February 2010

Key publications

2008

• Quivy J.P., Gérard A., Cook A.J.L., Roche D., Moné M. & Almouzni G
  The HP1-p150/CAF-1 is required for pericentric heterochromatin replication and S-phase progression in mouse cells
  Nature Struct. & Mol. Biol., 15, 972–979

2007

• Groth A., Corpet A., Cook A., Roche D., Bartek J., Lukas J. & Almouzni G.
  Regulation of replication fork progression through histone supply/demand
  Science, 318, 1928-1931 - Abstract
  http://www.sciencemag.org/cgi/content/abstract/318/5858/1928?ijkey=HkuNrgAJvA1ck&keytype=ref&siteid=sci
  - Full version
• De Koning L., Corpet A., Haber J.E. & Almouzni G.
  Histone chaperons : An escort network regulating histone traffic
  Nature Struct. & Mol. Biol., 14, 997-1007
• Groth A., Rocha W., Verreault A. & Almouzni G.
  Chromatin challenges during DNA replication and repair
  Cell, 128, 721-733 - Full version

2006

• Polo S., Roche D. & Almouzni G.
  Evidence for new histone incorporation marking sites of UV-repair in human cells
  Cell, 127, 481-493
• Loyola A., Bonaldi T., Roche D., Imhof A. & Almouzni G.
  PTMs on H3 variants before chromatin assembly potentiate their final epigenetic state
  Molecular Cell, 24, 309-316