Sposito, Teresa;
(2020)
Histone replacement in cancer: dissecting the role of H3.3 chaperone DAXX in pancreatic tumorigenesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Progressive age-dependent replacement of canonical H3.1/2 with H3.3 in post-mitotic cells is a crucial mechanism for maintaining genome integrity. The histone chaperone DAXX cooperates with the chromatin remodeller ATRX for the deposition of the non-canonical histone H3.3 at heterochromatin; while it prevents the expression of endogenous retroviral elements in another complex involving the SETDB1 methyltransferases. Loss of functions mutations affecting ATRX/DAXX and MEN-1 have been recently identified as a subgroup of pancreatic neuroendocrine tumours (PanNETs) with an alpha cell-signature, leading to poor prognosis and more aggressive phenotype compared to the ATRX/DAXX and MEN-1 wild-type counterpart. This study introduces a new model of DAXX inactivation in pancreatic beta-cells to characterise the role of DAXX in pancreatic development/homeostasis since PanNETs harbouring loss of DAXX are associated with the shortest survival amongst mutants. Loss of DAXX in the endocrine pancreas, using the Insulin-1Cre driver, alters glucose metabolism due to reduced beta-cells fitness; nevertheless, it was not sufficient to drive tumour formation. To generate a tumour permissive environment, PTEN loss was also added to the Insulin-1Cre+/Daxx KO system, on the observed loss of mTOR regulators in 14% of PanNETs. DAXX and PTEN synergistic loss in pancreatic islets promote the development of PanNET hallmarks such as cell-fate reprogramming and inflammation. Overall this study suggests that alteration of pancreatic homeostasis and inflammation precede/predispose to neoplastic transformation.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Histone replacement in cancer: dissecting the role of H3.3 chaperone DAXX in pancreatic tumorigenesis |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | DAXX, Histone chaperone, Epigenetic, PanNET |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10093625 |
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