Project description
Elucidating the molecular mechanisms and dynamics of histone modifications
Cellular identity is defined by complex patterns of DNA and histone modifications, which have to be tightly regulated during the cell cycle. Loss of cellular identity promotes different diseases including neurological disorders and cancer. The molecular mechanisms of histone modifications that spread along chromatin and can be transmitted through cell division are not well understood and require techniques that will allow their study in real-time. The EU-funded DYMOCHRO project aims to elucidate the fundamental principles of histone modification dynamics governing the establishment and preservation of cellular identity. The study will use innovative chromatin curtains technology to visualise the spreading and maintenance of histone methylation to directly assess the dynamics of histone modification patterns on single chromatin fibres under native conditions.
Objective
Cellular identity is defined by complex patterns of DNA and histone modifications, which partition our chromosomes and determine how cells interpret the genetic information. For cells to remember who they are, these modifications have to be tightly regulated over time and through cell division. Loss of cellular identity promotes different types of disease including neurological disorders and cancer.
Histone modifications can spread along chromatin and can be transmitted through cell division, giving rise to chromatin position effects and cellular memory. However, the underlying molecular mechanisms are not understood. In particular, we do not know how the size and stability of modified domains is controlled, and we currently lack techniques to study these processes in real-time.
Here, I propose to develop the single-molecule ‘chromatin curtains’ platform to directly visualize spreading and maintenance of histone methylation in a reconstituted system and to compare the resulting domains to those found on individual chromatin fibers isolated from cells. In a complementary approach, I will devise and set up a tunable synthetic circuit that installs and reinforces orthogonal epigenetic modifications in living cells to define the functional modules that are necessary and sufficient for chromatin position effects and cellular memory.
My project combines molecular biophysics with synthetic biology to elucidate the fundamental principles that govern the dynamics of histone modifications to establish and preserve cellular identity. The chromatin curtains platform I will develop complements sequencing-based methods and will make it for the first time possible to directly assess the dynamics of histone modification patterns on single chromatin fibers under native conditions. I anticipate that the insights gained in my project will aid in the design of future strategies to control histone modifications in disease.
Fields of science
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Funding Scheme
ERC-STG - Starting GrantHost institution
75794 Paris
France