@article{1873637b426c41649db60ed4e88c59f2,
title = "Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo",
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.",
author = "Wasylishen, {Amanda R.} and Chang Sun and Moyer, {Sydney M.} and Yuan Qi and Chau, {Gilda P.} and Aryal, {Neeraj K.} and Florencia McAllister and Kim, {Michael P.} and Barton, {Michelle C.} and Estrella, {Jeannelyn S.} and Xiaoping Su and Guillermina Lozano",
note = "Funding Information: The Atrx conditional knockout mouse was provided by R. Gibbons. We thank S. Arur, N. Copeland, N. Jenkins, and A. Maitra, as well as members of the Lozano laboratory for helpful discussions. We also acknowledge Scientific Publications, Research Medical Library at MD Anderson for editing this manuscript. This research was supported by grants from the Neuroendocrine Tumor Research Foundation and NIH (NIH/NCI R21 CA208463) to G.L. and a fellowship from the Canadian Institutes of Health Research to A.R.W. Sequencing experiments were performed with The MD Anderson Advanced Technology Genomics Core and gene targeting to generate the Daxxfl allele was conducted by The MD Anderson Genetically Engineered Mouse Facility. Both core facilities were supported, in part, by a Cancer Center Support Grant from the National Cancer Institute (CA016672). Publisher Copyright: Copyright {\textcopyright} 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = aug,
doi = "10.1126/sciadv.aba8415",
language = "English (US)",
volume = "6",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "32",
}