Julian Sale

How cells retain epigenetic memory in the face of replication stress
Group Leader page

Accurate replication of the genome must be accompanied by faithful propagation of the transcriptional programme programme of the cell. Key information determining which genes are expressed and which are silenced is encoded epigenetically in post-translational modifications of histone proteins and the ability to propagate these modifications through DNA replication has been proposed to be critical for maintaining transcriptional states [1]. Over the past few years we have shown that replication impediments caused by DNA secondary structures [2] can disrupt histone recycling leading to localised, stochastic loss of epigenetic information and dysregulation of both active and repressed loci [3-6].

Mechanisms have been established for how histone recycling contributes to the propagation of repressive chromatin states, characterised by methylation of histone H3 on lysines 9 and 27 [1]. However, why it is needed for maintaining active gene expression is not understood.

The project will investigate the underlying mechanisms by which stable, active gene expression is maintained during replication and how cells maintain this epigenetically-determined state in the face of stresses to replication. The project will focus on the H3K4me3 histone mark and its potential role in retention of active transcriptional memory aiming to understand why it is sensitive to replication impediments.

The project will combine somatic cell genetics using both conventional gene targeting and Cas9/CRISPR technology to manipulate specific DNA secondary structure replication blocks. This will be combined with state of the art methods to interrogate and control local epigenetic states, in particular potential mechanisms that help propagate H3K4me3.

Further information on the work of the group can be found on our web page.


References:

  1. Sarkies, P. and Sale, J.E. (2012).
    Propagation of histone marks and epigenetic memory during normal and interrupted DNA replication.
    Cell Mol Life Sci 69, 697-716.
  2. Wickramasinghe, C.M., Arzouk, H., Frey, A., Maiter, A. and Sale, J.E. (2015).
    Contributions of the specialised DNA polymerases to replication of structured DNA.
    DNA Repair 23, 83-90.
  3. Sarkies, P., Reams, C., Simpson, L.J. and Sale, J.E. (2010)
    Epigenetic instability due to defective replication of structured DNA.
    Molecular Cell, 40, 703-713.
  4. Schiavone, D., Guilbaud, G., Murat, P., Papadopoulou, C., Sarkies, P., Prioleau, M.-N., Balasubramanian, S. and Sale, J.E. (2014)
    Determinants of G quadruplex-induced epigenetic instability in REV1-deficient cells.
    EMBO J. 33, 2507-2520.
  5. Papadopoulou, C., Guilbaud, G., Schiavone, D. and Sale J.E. (2015).
    G quadruplexes potentiate replication stress-induced epigenetic instability.
    Cell Reports 13, 2491-503. doi: 10.1016/j.celrep.2015.11.039. 
  6. Schiavone, D., Jozwiakowski, S.K., Romanello, M., Guilbaud, G., Bailey, L.J., Sale, J.E. & Doherty, A.J. (2016).
    PrimPol is required for replicative tolerance of G quadruplexes in vertebrate cells.
    Molecular Cell 61, 161-169.