Sophie Polo’s group studies chromatin plasticity in response to DNA damage in mammalian cells. Research in her lab focuses on identifying the molecular players that control histone dynamics, alterations in chromatin marks and higher-order chromatin structure and function in response to genotoxic stress. By combining molecular and cellular approaches with cutting-edge imaging techniques, they are interested in understanding how genome and epigenome maintenance are coordinated.
CURRENT RESEARCH AREAS
Genome integrity is constantly jeopardized by exogenous and endogenous sources of DNA damage, including radiations, chemicals and products of cell metabolism. In addition to its detrimental effects on DNA molecules, genotoxic stress also elicits marked alterations of DNA organization into chromatin. These rearrangements prime chromatin for repair and help restore its integrity (Figure 1). They involve the disorganization and subsequent re-organization of chromatin structure, the mechanisms of which are still incompletely understood.
It is unclear to which extent and for how long the chromatin landscape is altered in the vicinity of DNA lesions in terms of histone variants, histone and DNA modifications and chromatin compaction. This is a critical issue given the importance of epigenome integrity in safeguarding cell function and identity. Epigenome alterations indeed contribute to the development of diseases such as cancer.
In this context, we are interested in understanding how the information conveyed by chromatin structure is preserved when challenged by genotoxic stress and how genome and epigenome maintenance are coordinated in physiological conditions and during tumorigenesis.
For this, we investigate DNA damage-induced alterations at distinct levels of chromatin organization in mammalian cells, from histone proteins up to higher-order chromatin structure, and we explore the underlying mechanisms (Figures 2 & 3).
Our main goals are:
- To profile dynamic alterations in epigenetics marks (i.e. DNA and histone modifications) upon DNA damage.
- To dissect the mechanisms underlying the maintenance of higher-order chromatin domains in the cell nucleus following genotoxic stress .
- To characterize the impact of epigenome alterations (histone oncomutations) on genome stability.
Our experimental approaches:
We combine molecular and cellular approaches with advanced microscopy techniques to investigate chromatin dynamics in response to genotoxic stress in cultured mammalian cells. In particular, we couple local induction of DNA damage in live cell nuclei (Figure 4) with in vivo tracking of histone proteins using the SNAP-tag technology.
We also develop complementary approaches for isolating repair patches to analyze local alterations in epigenetic marks and larger scale changes in damaged chromatin organization.
Figure 4: Local induction of DNA damage in cultured cells by UVC irradiation (from Adam & Polo, Int J Mol Sci 2012)
Fortuny A., Chansard A., Caron P., Chevallier O., Leroy O., Renaud O., Polo S.E. Imaging the response to DNA damage in heterochromatin domains reveals core principles of heterochromatin maintenance. Nat Commun 2021, 12: 2428.
Piquet S., Le Parc F., Bai, S-K., Chevallier O., Adam S., Polo S.E. The histone chaperone FACT coordinates H2A.X-dependent signaling and repair of DNA damage. Mol Cell, 72: 888-901, 2018.
Dabin J.*, Fortuny A.*, Piquet S, Polo S.E. Live imaging of parental histone variant dynamics in UVC-damaged chromatin. Methods Mol Biol, 1832: 243-253, 2018. *: equal contribution
Fortuny A, Polo S.E. The response to DNA damage in heterochromatin domains. Chromosoma, 127: 291-300, 2018.
Adam S.*, Dabin J.*, Chevallier O., Leroy O., Baldeyron C., Corpet A., Lomonte P., Renaud O., Almouzni G. and Polo S.E. Real-time tracking of parental histones reveals their contribution to chromatin integrity following DNA damage. Mol Cell, 64: 65-78, 2016. *: equal contribution. Featured article, also highlighted in the “Meet the author” section.
Dabin J.*, Fortuny A.* and Polo S.E. Epigenome maintenance in response to DNA damage. Mol Cell, 62:712-727, 2016. *: contribution equivalente
Adam S.*, Dabin J.*, Bai S-K. & Polo S.E. Imaging local deposition of newly synthesized histones in UVC-damaged chromatin. Methods Mol Biol, 1288:337-347, 2015. *: contribution equivalente
Adam S., Polo S.E.* & Almouzni G.* Transcription recovery after DNA damage requires chromatin priming by the H3.3 histone chaperone HIRA. Cell, 155: 94-106, 2013.*: co-corresponding auteurs