Genomic functions of developmental pluripotency associated factor 4 (Dppa4) in pluripotent stem cells and cancer

Stem Cell Res. 2018 Aug;31:83-94. doi: 10.1016/j.scr.2018.07.009. Epub 2018 Jul 19.


Developmental pluripotency associated factor 4 (Dppa4) is a highly specific marker of pluripotent cells, and is also overexpressed in certain cancers, but its function in either of these contexts is poorly understood. In this study, we use ChIP-Seq to identify Dppa4 binding genome-wide in three distinct cell types: mouse embryonic stem cells (mESC), embryonal carcinoma cells, and 3T3 fibroblasts ectopically expressing Dppa4. We find a core set of Dppa4 binding sites shared across cell types, and also a substantial number of sites unique to each cell type. Across cell types Dppa4 shows a preference for binding to regions with active chromatin signatures, and can influence chromatin modifications at target genes. In 3T3 fibroblasts with enforced Dppa4 expression, Dppa4 represses the cell cycle inhibitor Cdkn2c and activates Ets family transcription factor Etv4, leading to alterations in the cell cycle that likely contribute to the oncogenic phenotype. Dppa4 also directly regulates Etv4 in mESC but represses it in this context, and binds with Oct4 to a set of shared targets that are largely independent of Sox2 and Nanog, indicating that Dppa4 functions independently of the core pluripotency network in stem cells. Together these data provide novel insights into Dppa4 function in both pluripotent and oncogenic contexts.

Keywords: Cell cycle; Chromatin; Dppa4; Histone deacetylase; Oct4; Oncogene; Pluripotent stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / metabolism
  • Animals
  • Cell Proliferation / physiology
  • Chromatin / genetics
  • Chromatin / metabolism
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • Cyclin-Dependent Kinase Inhibitor p18 / metabolism
  • Embryonal Carcinoma Stem Cells / cytology
  • Embryonal Carcinoma Stem Cells / metabolism
  • Embryonal Carcinoma Stem Cells / physiology*
  • Gene Expression Regulation
  • Genomics / methods
  • Humans
  • Mice
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism
  • Pluripotent Stem Cells / physiology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / metabolism
  • Transfection


  • Adenovirus E1A Proteins
  • Chromatin
  • Cyclin-Dependent Kinase Inhibitor p18
  • DPPA4 protein, human
  • Dppa4 protein, mouse
  • ETV4 protein, human
  • Etv4 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets