2. Academic Validation
  3. Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo

Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo

  • Sci Adv. 2020 Aug 5;6(32):eaba8415. doi: 10.1126/sciadv.aba8415.
Amanda R Wasylishen 1,  Chang Sun 1 2,  Sydney M Moyer 1 2,  Yuan Qi 3,  Gilda P Chau 1,  Neeraj K Aryal 1 2,  Florencia McAllister 4,  Michael P Kim 5,  Michelle C Barton 2 6,  Jeannelyn S Estrella 7,  Xiaoping Su 3,  Guillermina Lozano 1 2
Affiliations

Affiliations

  • 1 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2 Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
  • 3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 5 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 6 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 7 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
PMID: 32821827 DOI: 10.1126/sciadv.aba8415
Abstract

Tumor sequencing studies have emphasized the role of Epigenetics and altered chromatin homeostasis in Cancer. Mutations in DAXX, which encodes a chaperone for the histone 3.3 variant, occur in 25% of pancreatic neuroendocrine tumors (PanNETs). To advance our understanding of physiological functions of Daxx, we developed a conditional Daxx allele in mice. We demonstrate that Daxx loss is well tolerated in the pancreas but creates a permissive transcriptional state that cooperates with environmental stress (inflammation) and other genetic lesions (Men1 loss) to alter gene expression and cell state, impairing pancreas recovery from inflammatory stress in vivo. The transcriptional changes are associated with dysregulation of endogenous retroviral elements (ERVs), and dysregulation of endogenous genes near ERVs is also observed in human PanNETs with DAXX mutations. Our results reveal a physiologic function of DAXX, provide a mechanism associated with impaired tissue regeneration and tumorigenesis, and expand our understanding of ERV regulation in somatic cells.

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