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The Mattiroli group studies chromatin dynamics during DNA replication to understand how the epigenetic information is faithfully propagated during cell division.
In eukaryotes, chromatin organizes the genetic and epigenetic information of the cell. The epigenetic information ensures the spatial and timely organization of gene transcription that determines cell identity. Aberrant regulation of the epigenetic information results in changes in cell fate decisions, thereby affecting development and tissue homeostasis, and ultimately leading to disease, such as cancer.
During cell division, accurate propagation of the epigenetic information is thus essential for cell survival and disease avoidance. While we understand how the genetic information is replicated in S phase, we lack mechanistic knowledge on how the epigenetic information, specifically histone post-translational modifications in nucleosomes, are propagated to daughter cells.
We use structural approaches (i.e. X-ray crystallography, hydrogen-deuterium exchange, multi-angle light scattering), biochemical and biophysical methods (i.e. recombinant assays and reconstitutions, in vitro binding studies, fluorescence-based assays), and cell biology techniques (i.e. immunofluorescence, immunoprecipitations) to study the mechanism of chromatin duplication, and we aim to understand how chromatin duplication affects cellular life and disease development.
After DNA replication, nucleosome density is maintained by incorporating newly synthesized histones besides the recycling of parental histones (Figure 1). In this process, the parental epigenetic modifications are diluted and need to be properly re-established on the daughter strands to control cell fate and to avoid disease development. We study the molecular network that controls chromatin duplication using biochemical reconstitutions and cell biology in yeast and human cells. These pathways are interconnected with cell cycle control and DNA damage response.
Nucleosomes are disassembled and reassembled during DNA replication to ensure a faithful copy on each daughter strand. A variety of histone chaperones are involved in these dynamics, but how these activities are integrated in this process remains largely unclear.
We have developed a quantitative nucleosome assembly (NAQ) assay that measures nucleosome formation in vitro (Figure 2). This assay enabled us to elucidate the mechanism of action of the chromatin assembly factor 1 (CAF-1), leading to the first described molecular model for nucleosome assembly (Figure 3) (1)(2).
CAF-1 orchestrates histone deposition and nucleosome assembly during DNA replication. We are now interested in understanding how this mechanism of action is coupled to the machineries that control genome duplication in S phase (Figure 1).
We primarily use structural and biochemical approaches to study the relevant interactions between CAF-1 and the replisome and to investigate their interplay with S phase and checkpoint signaling components.
1. DNA-mediated association of two histone-bound complexes of yeast Chromatin Assembly Factor-1 (CAF-1) drives tetrasome assembly in the wake of DNA replication.
Mattiroli F*, Gu Y*, Yadav T, Balsbaugh JL, Harry MR, Findlay ES, Liu Y, Radebaugh CA, Stargell LA, Ahn NG, Whitehouse I, Luger K.
Elife 2017 Mar;6. doi: 10.7554/eLife.22799.
2. The Cac2 subunit is essential for productive histone binding and nucleosome assembly in CAF-1.
Mattiroli F*, Gu Y*, Balsbaugh JL, Ahn NG, Luger K.
Sci Rep. 2017 Apr;7:46274.
Mattiroli F*, Bhattacharyya S*, Dyer PN, White AE, Sandman K, Burkhart BW, Byrne KR, Lee T, Ahn NG, Santangelo TJ, Reeve JN, Luger K
Mattiroli F*, Gu Y*, Yadav T, Balsbaugh JL, Harry MR, Findlay ES, Liu Y, Radebaugh CA, Stargell LA, Ahn NG, Whitehouse I, Luger K
Mattiroli F*, Gu Y*, Balsbaugh JL, Ahn NG, Luger K
Mattiroli F*, Uckelmann M*, Sahtoe DD, van Dijk WJ, Sixma TK
Mattiroli F, Vissers JHA, van Dijk WJ, Ikpa P, Citterio E, Vermeulen W, Marteijn JA, Sixma TK
Mallette FA, Mattiroli F, Cui G, Young LC, Hendzel MJ, Mer G, Sixma TK, Richard S
Francesca Mattiroli is a group leader at the Hubrecht Institute since January 2018. Her group investigates the mechanisms that control inheritance of the epigenetic information contained in nucleosomes, during cell division and in situation of DNA damage. The Mattiroli group integrates biochemical, structural and cell biology approaches. They use recombinant reconstitutions of chromatin replication and study the biophysical and structural properties of key protein-protein interactions and their functions. These studies will reveal how cells control fate and survival, paving the way to potential novel therapeutic strategies in cancer and other diseases.
Scientific training and positions
Utrecht Science Park, De Uithof
Utrecht Science Park, De Uithof.