Daxx maintains endogenous retroviral silencing and restricts cellular plasticity in vivo

Daxx loss causes coordinate dysregulation of ERVs and protein-coding genes after physiologic stress and impairs tissue recovery. 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.

[1]  Y. Qi,et al.  Men1 maintains exocrine pancreas homeostasis in response to inflammation and oncogenic stress , 2020, Proceedings of the National Academy of Sciences.

[2]  Daiqing Liao,et al.  DAXX in cancer: phenomena, processes, mechanisms and regulation , 2019, Nucleic acids research.

[3]  M. Gonzalo Claros,et al.  Expression Change Correlations Between Transposons and Their Adjacent Genes in Lung Cancers Reveal a Genomic Location Dependence and Highlights Cancer-Significant Genes , 2019, IWBBIO.

[4]  V. Pant,et al.  Daxx Functions Are p53-Independent In Vivo , 2018, Molecular Cancer Research.

[5]  Y. Shinkai,et al.  A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing , 2018, Nature Communications.

[6]  Hu Li,et al.  Global H3.3 dynamic deposition defines its bimodal role in cell fate transition , 2018, Nature Communications.

[7]  C. Miller,et al.  Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling , 2018, Nature Communications.

[8]  Nicholas A. Sinnott-Armstrong,et al.  An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues , 2017, Nature Methods.

[9]  Heiko Lickert,et al.  Cellular and molecular mechanisms coordinating pancreas development , 2017, Development.

[10]  Steven J. M. Jones,et al.  Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. , 2017, Cancer cell.

[11]  Shivashankar H. Nagaraj,et al.  Whole-genome landscape of pancreatic neuroendocrine tumours , 2017, Nature.

[12]  Xiaoping Su,et al.  Expression of human endogenous retrovirus-K is strongly associated with the basal-like breast cancer phenotype , 2017, Scientific Reports.

[13]  G. Schotta,et al.  Silencing of endogenous retroviruses by heterochromatin , 2017, Cellular and Molecular Life Sciences.

[14]  Samuel L. Wolock,et al.  A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure. , 2016, Cell systems.

[15]  Mauro J. Muraro,et al.  A Single-Cell Transcriptome Atlas of the Human Pancreas , 2016, Cell systems.

[16]  Helen M. Rowe,et al.  Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues. , 2016, Developmental cell.

[17]  Robert D. Finn,et al.  The Dfam database of repetitive DNA families , 2015, Nucleic Acids Res..

[18]  Aaron T. L. Lun,et al.  csaw: a Bioconductor package for differential binding analysis of ChIP-seq data using sliding windows , 2015, Nucleic acids research.

[19]  C. Allis,et al.  Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells , 2015, Nature.

[20]  M. Hebrok,et al.  Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease. , 2015, Cell stem cell.

[21]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[22]  L. Howells,et al.  Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. , 2014, European journal of cancer.

[23]  Paul Theodor Pyl,et al.  HTSeq—a Python framework to work with high-throughput sequencing data , 2014, bioRxiv.

[24]  A. Maitra,et al.  Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. , 2014, Cancer cell.

[25]  H. Lee,et al.  Experimental Models of Pancreatitis , 2014, Clinical endoscopy.

[26]  Andreas Krämer,et al.  Causal analysis approaches in Ingenuity Pathway Analysis , 2013, Bioinform..

[27]  M. Stratton,et al.  Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone , 2013, Nature Genetics.

[28]  Peter W. Laird,et al.  Interplay between the Cancer Genome and Epigenome , 2013, Cell.

[29]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[30]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[31]  Bronwen L. Aken,et al.  GENCODE: The reference human genome annotation for The ENCODE Project , 2012, Genome research.

[32]  Peter A. Jones,et al.  Cancer genetics and epigenetics: two sides of the same coin? , 2012, Cancer cell.

[33]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[34]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[35]  Brian J. Stevenson,et al.  Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. , 2012, Genome research.

[36]  David T. W. Jones,et al.  Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma , 2012, Nature.

[37]  T. Ohtsuka,et al.  Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development , 2011, Neuroscience Research.

[38]  R. McLendon,et al.  Altered Telomeres in Tumors with ATRX and DAXX Mutations , 2011, Science.

[39]  Steven J. M. Jones,et al.  DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. , 2011, Cell stem cell.

[40]  Michael A. Choti,et al.  DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors , 2011, Science.

[41]  S. Libutti,et al.  Multiple endocrine neoplasia type 1 deletion in pancreatic alpha-cells leads to development of insulinomas in mice. , 2010, Endocrinology.

[42]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[43]  P. Herrera,et al.  Alpha cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development. , 2010, Gastroenterology.

[44]  S. Rafii,et al.  Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions , 2010, Cell.

[45]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[46]  S. Libutti,et al.  Recapitulation of pancreatic neuroendocrine tumors in human multiple endocrine neoplasia type I syndrome via Pdx1-directed inactivation of Men1. , 2009, Cancer research.

[47]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[48]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[49]  D. Higgs,et al.  Loss of Atrx Affects Trophoblast Development and the Pattern of X-Inactivation in Extraembryonic Tissues , 2006, PLoS genetics.

[50]  R. Paro,et al.  Suppression of Polycomb group proteins by JNK signalling induces transdetermination in Drosophila imaginal discs , 2005, Nature.

[51]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[52]  O. Rozenblatt-Rosen,et al.  Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[53]  G. Kay,et al.  Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. , 2004, Molecular cell.

[54]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[55]  D. Hanahan,et al.  Of Mice and MEN1: Insulinomas in a Conditional Mouse Knockout , 2003, Molecular and Cellular Biology.

[56]  F. Collins,et al.  A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[57]  P. Leder,et al.  Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. , 1999, Genes & development.

[58]  F. Collins,et al.  Menin Interacts with the AP1 Transcription Factor JunD and Represses JunD-Activated Transcription , 1999, Cell.

[59]  G. Karsenty,et al.  The mouse osteocalcin gene cluster contains three genes with two separate spatial and temporal patterns of expression. , 1994, The Journal of biological chemistry.