Naive Human Pluripotent Cells Feature a Methylation Landscape Devoid of Blastocyst or Germline Memory

Cell Stem Cell. 2016 Mar 3;18(3):323-329. doi: 10.1016/j.stem.2016.01.019. Epub 2016 Feb 4.


Human embryonic stem cells (hESCs) typically exhibit "primed" pluripotency, analogous to stem cells derived from the mouse post-implantation epiblast. This has led to a search for growth conditions that support self-renewal of hESCs akin to hypomethylated naive epiblast cells in human pre-implantation embryos. We have discovered that reverting primed hESCs to a hypomethylated naive state or deriving a new hESC line under naive conditions results in the establishment of Stage Specific Embryonic Antigen 4 (SSEA4)-negative hESC lines with a transcriptional program resembling the human pre-implantation epiblast. In contrast, we discovered that the methylome of naive hESCs in vitro is distinct from that of the human epiblast in vivo with loss of DNA methylation at primary imprints and a lost "memory" of the methylation state of the human oocyte. This failure to recover the naive epiblast methylation landscape appears to be a consistent feature of self-renewing hypomethylated naive hESCs in vitro.

Publication types

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

MeSH terms

  • Animals
  • Blastocyst / cytology
  • Blastocyst / metabolism*
  • Cell Line
  • DNA Methylation*
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism*
  • Humans
  • Mice
  • Oocytes / cytology
  • Oocytes / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Stage-Specific Embryonic Antigens / metabolism


  • Stage-Specific Embryonic Antigens
  • stage-specific embryonic antigen-4