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Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo

Amanda R Wasylishen1, Chang Sun1,2, Sydney M Moyer1,2

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Science Advances
|August 22, 2020
PubMed

Insights

Loss of DAXX in the pancreas creates a permissive state that impairs tissue repair and promotes tumorigenesis, particularly when combined with inflammation or Men1 loss. This involves dysregulation of endogenous retroviral elements.

Area of Science:

  • Molecular biology
  • Cancer research
  • Epigenetics

Background:

  • Tumor sequencing highlights epigenetics and chromatin in cancer.
  • DAXX mutations are found in 25% of pancreatic neuroendocrine tumors (PanNETs).
  • DAXX is a chaperone for the histone 3.3 variant.

Purpose of the Study:

  • To investigate the physiological functions of DAXX.
  • To understand DAXX's role in pancreas homeostasis and tumorigenesis.

Main Methods:

  • Development of a conditional DAXX allele in mice.
  • Analysis of pancreas recovery from inflammatory stress in vivo.
  • Examination of gene expression changes and endogenous retroviral element (ERV) regulation.

Main Results:

  • DAXX loss is tolerated in the pancreas but alters gene expression.
  • DAXX loss impairs pancreas recovery from inflammatory stress, especially with Men1 loss.
  • Transcriptional changes involve dysregulation of ERVs and nearby endogenous genes.

Conclusions:

  • DAXX plays a physiological role in pancreas tissue regeneration.
  • DAXX dysregulation contributes to tumorigenesis via altered gene expression and ERV regulation.
  • Findings provide insights into ERV regulation in somatic cells and PanNET development.

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