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How do cells divide? Chromatin re-organisation from mitosis to G1

Ongoing

Project description

Cell division is a fundamental process that is at the basis of our existence. From the single cell of a zygote, about 37.2 trillion cells are generated to make up an adult human being. Divisions need to occur in an extremely accurate manner in order to produce daughter cells that are healthy and viable but also to set up the topological cues for differentiation and organ geometry. Defects in cell division have been shown to be at the basis of several human pathologies. For example, incorrect segregation of chromosomes is the cause of microcephaly if it occurs during brain development, Down syndrome if it occurs in meiosis and cancer if it occurs in adulthood.

The long-term goal of my research is to understand the molecular basis of how chromosome structure and dynamics during mitotic exit direct the reformation of a functional G1 nucleus and how protein de-phosphorylation regulates this process in space and time.

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Multicellular organisms are composed of many types of specialised cells characterised by a specific gene expression program, different for each cell type. These specific programs must be maintained through generations and transmitted from mother to daughter cells. Cell division (Mitosis) poses a challenge to cellular identity because, during this complex process, the entire genome is repackaged into mitotic chromosomes, the Nuclear Envelope (NE) is disassembled, and transcription and translation are diminished. If cell identity is to be preserved, a cell-specific organisation must be restored, and gene expression resumed efficiently and faithfully following mitosis.

After cell division, the cell needs to re-build the nucleus: the chromatin de-condenses; chromatin-binding proteins need to re-bind to their respective docking sites; the nuclear membrane and nuclear-cytoplasmic transport are restored; finally, the chromosomes are re-organised to their interphase territory arrangements, and they establish attachments to the nuclear membrane or to newly re-assembled nuclear structures. This is key in ensuring the successful transmission of specialised cellular function vital to controlling human health, both during embryonic growth and later in life.

Despite the importance of these processes and their translational potential, we are still missing an integrated view of the underlying molecular mechanisms. Gaining an overall understanding of the processes underlying the transmission of cellular identity through generations is a fundamental question in cell biology. This understanding will open up the possibility of intervening to correct anomalies in defective cells. Moreover, elucidating the mechanisms which control the differentiated state will open up entirely new possibilities both for treating cells (such as cancer cells) which have lost their identity and for the generation of iPSCs (induced pluripotent stem cells) or other specific and clinically-relevant cell lineages.