Histone Replacement in Cancer: Dissecting the Role of H3.3 Chaperones in Pancreatic Tumorigenesis Abstract #2126

Introduction: Cancer driver mutations affecting the histone H3.3 chromatin remodellers ATRX and DAXX were recently discovered in 43% of sporadic pancreatic neuroendocrine tumours (PNET). Progressive age-dependent replacement of canonical H3.1/2 with H3.3 is crucial for maintaining genome integrity through expression of repressive markers at heterochromatic sites, where loading is mediated by ATRX and DAXX. Loss of H3.3 chaperones in PNET is associated with activation of ALT, a telomere maintenance mechanism, eventually leading to chromosome instability. It has been suggested that ATRX/DAXX expression is necessary for repressing ALT, but mechanistic details of this interaction are not fully understood.
Aim(s): Our aim is to dissect the role of DAXX in pancreatic development, homeostasis and tumorigenesis.
Materials and methods: The Insulin-1 Cre line which constitutively expresses Cre under the control of Insulin-1 promoter was crossed with DAXX conditional line, leading to DAXX loss in pancreatic β-cells. We are now investigating the impact of DAXX loss on β-cell homeostasis using primary islet cultures and pancreas tissue analysis. In addition, we are utilising a reporter gene for Cre expression to purify DAXX knock-out β-cells and perform molecular analyses to associate changes at chromatin and transcriptional level with potential phenotypes.
Conference: 15th Annual ENETS conference (2018)
Category: Basic Science - In vitro models, tumor growth, CTCs
Presenting Author: PhD Student Teresa Sposito

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