The genome of the fertilised zygote undergoes rapid remodelling in order to develop into a multicellular embryo. Of these events, the reprogramming of chromatin is essential to generate totipotency - the capacity to form the whole organism including all embryonic and extraembryonic cell types. A similar reprogramming process is repeated in the context of the early developing germ line that will eventually generate sperm and eggs. Understanding these processes is essential to learn how normal development occurs. Moreover, it may shed light on pathologies linked to defective chromatin regulation, such as cancer, infertility, and aging.
Despite its importance, how chromatin remodelling is regulated during development is still poorly understood. In particular, descriptions of chromatin packaging or structure have consisted primarily of in vitro or cell-free assays and reconstitutions, which may not faithfully recapitulate the organisation of chromatin in cells (1). Within cells, electron microscopy (EM) studies provide the highest resolution, yet they have been limited to single snapshots through cross-sections of cells and tissues, in samples fixed and stained with heavy metals. We therefore still do not have a clear picture of what native chromatin looks like in situ, as well as how this changes dynamically in development and disease.
In this project, the successful PhD student use in-cell cryo-EM to characterise how chromatin structure is established and remodelled during mouse early development and germ cell development. The studentship is a new collaboration between the ICS at Imperial College London and the Rosalind Franklin Institute (RFI). The student will uniquely benefit from the combined expertise in early development and chromatin regulation at the ICS (Hajkova & Percharde) and cutting edge in-cell EM at the RFI (Naismith). They will use new equipment at the MRC LMS for cryogenic Correlative Light and Electron Microscopy (cryo-CLEM(2)) and serial block face scanning electron microscope (SBF-SEM) imaging. The student will take advantage of the latest cryogenic EM techniques to visualise chromatin in native conditions in cells and tissues, and answer questions such as how does chromatin architecture change during reprogramming(3) or in pathologies such as aging. This is an excellent opportunity for an ambitious student wanting to work in the forefront of epigenetics and in-cell structural biology.
Links
https://www.rfi.ac.uk/science-themes/structural-biology/
www.perchardelab.com
https://lms.mrc.ac.uk/research-group/reprogramming-and-chromatin/
https://lms.mrc.ac.uk/research-group/chromatin-and-development/
To apply for this programme please visit the LMS website where the application form is available for download - https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/
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