Patrick Varga-Weisz
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• Recent, selected Publications
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Chromatin remodelling factors in chromatin dynamics
We are interested in the machinery that renders chromatin a highly dynamic structure, to accommodate its many tasks in regulating, organising, safeguarding and packaging the genetic material. Key components that impart this dynamic state are special enzymes, so-called chromatin remodelling factors, many of which target the nucleosome, the basic building block of chromatin.
One particular class of chromatin remodelling factors uses the energy gained by ATP hydrolysis to remodel nucleosomes: the nucleosome may be shifted, altered or blasted away. This reaction in turn allows access of other proteins to chromatin, for example transcriptional activators that turn-on genes. ATP-dependent chromatin remodelling factors, such as Imitation Switch (ISWI), are also involved in nucleosome assembly. The Varga-Weisz laboratory studies ATP-dependent nucleosome remodelling factors, their role in the cell and their mechanisms of action.
ISWI is a nucleosome specific ATPase that ‘pushes’ nucleosomes along the DNA. ISWI-containing nucleosome remodelling complexes are involved in many aspects of nuclear functions, such as transcription and chromosome structure maintenance. We provided evidence for a role of ISWI in facilitating DNA replication through heterochromatin and in chromatin replication itself.
Figure 1 (Click to enlarge)
The W STF- I SWI chromatin remodelling (WICH) complex interacts with PCNA,
a sliding protein ring around the DNA that forms at the DNA replication site.
Recently we have shown that one specific ISWI-complex (the WICH-complex) is targeted to DNA replication sites through the interaction of its subunit WSTF (Williams Syndrome Transcription Factor) with the sliding DNA clamp, PCNA. This work identified a fundamentally different targeting mechanism of ATP-dependent nucleosome remodelling factors from the previously documented targeting by site specific transcriptional regulators (Figure 1). Without WSTF, chromatin turns out to be generally more condensed after DNA replication. We hypothesize that WSTF and probably other factors are required to reset chromatin structure after DNA replication by allowing factors, such as transcriptional regulators, to rebind to the chromatin after the replication fork perturbed their interaction with chromatin (Figure 2).
Figure 2 (Click to enlarge)
A model to explain why WICH may be required for chromatin replication.
Future work will address the mechanisms by which ISWI-complexes are involved in chromatin replication. Furthermore, we want to work towards a more comprehensive understanding of the ‘tool box’ that is required to have dynamic chromatin.
Recent, selected publications
Varga-Weisz PD, Becker PB (2006)
Regulation of higher-order chromatin structures by nucleosome-remodelling factors.
Current Opinion in Genetics and Development 16 151-156
http://dx.doi.org/10.1016/j.gde.2006.02.006
Poot RA, Bozhenok L, Van den Berg DLC, Hawkes N, Varga-Weisz PD (2005) Chromatin remodeling by WSTF-ISWI at the replication site: opening a window of opportunity for epigenetic inheritance?
Cell Cycle 4 543-546
http://www.landesbioscience.com/journals/cc/article/pootCC4-4.pdf
Kukimoto I, Elderkin S, Grimaldi M, Oelgeschläger T, Varga-Weisz PD (2004) The histone-fold protein complex CHRAC-15/17 enhances nucleosome sliding and assembly mediated by ACF.
Molecular Cell 13 265-277
http://dx.doi.org/10.1016/S1097-2765(03)00523-9
Poot RA, Bozhenok L, van den Berg DLC, ren Steffensen SA, Ferreira F, Grimaldi M, Gilbert N, Ferreira J, Varga-Weisz PD (2004) The Williams syndrome transcription factor interacts with PCNA to target chromatin remodelling by ISWI to replication foci.
Nature Cell Biology 6 1236-1244
http://dx.doi.org/10.1038/ncb1196
Bozhenok L, Wade PA, Varga-Weisz PD (2002) WSTF–ISWI chromatin remodeling complex targets heterochromatic replication foci.
EMBO Journal 21 2231-2241
http://dx.doi.org/10.1093/emboj/21.9.2231
Collins N, Poot RA, Kukimoto I, Garcia-Jimenez C, Dellaire G, Varga-Weisz PD (2002) An ACF1–ISWI chromatin-remodeling complex is required for DNA replication through heterochromatin.
Nature Genetics 32 627-632
http://dx.doi.org/10.1038/ng1046
Yasui D, Miyano M, Cai S, Varga-Weisz PD, Kohwi-Shigematsu T (2002) SATB1 targets chromatin remodelling to regulate genes over long distances.
Nature 419 641-645
http://dx.doi.org/10.1038/nature01084
Poot RA, Dellaire G, Hulsmann BB, Grimaldi MA, Corona DFV, Becker PB, Bickmore WA, Varga-Weisz PD (2000) HuCHRAC, a human ISWI chromatin remodelling complex contains hACF1 and two novel histone-fold proteins.
EMBO Journal 19 3377-3387
http://dx.doi.org/10.1093/emboj/19.13.3377
Group Members
Postdocs
Ross Miller
Ryan Will
PhD Students
Parul Choudhary
Cassandra Hogan
Ana Neves-Costa
Sam Rowbotham
Visitors
Anna Vetter
Maria Mallardo
