Nuclear transcriptome profiling of induced pluripotent stem cells and embryonic stem cells identify non-coding loci resistant to reprogramming

Cell Cycle. 2015;14(8):1148-55. doi: 10.4161/15384101.2014.988031.


Identification of functionally relevant differences between induced pluripotent stem cells (iPSC) and reference embryonic stem cells (ESC) remains a central question for therapeutic applications. Differences in gene expression between iPSC and ESC have been examined by microarray and more recently with RNA-SEQ technologies. We here report an in depth analyses of nuclear and cytoplasmic transcriptomes, using the CAGE (cap analysis of gene expression) technology, for 5 iPSC clones derived from mouse lymphocytes B and 3 ESC lines. This approach reveals nuclear transcriptomes significantly more complex in ESC than in iPSC. Hundreds of yet not annotated putative non-coding RNAs and enhancer-associated transcripts specifically transcribed in ESC have been detected and supported with epigenetic and chromatin-chromatin interactions data. We identified super-enhancers transcriptionally active specifically in ESC and associated with genes implicated in the maintenance of pluripotency. Similarly, we detected non-coding transcripts of yet unknown function being regulated by ESC specific super-enhancers. Taken together, these results demonstrate that current protocols of iPSC reprogramming do not trigger activation of numerous cis-regulatory regions. It thus reinforces the need for already suggested deeper monitoring of the non-coding transcriptome when characterizing iPSC clones. Such differences in regulatory transcript expression may indeed impact their potential for clinical applications.

Keywords: CAGE, cap analysis of gene expression; ENCODE, Encyclopedia of DNA Elements; ESC, embryonic stem cells; NAST, Non-Annotated Stem Transcripts; Stem cells; eRNA, enhancer RNA; iPS; iPSC, induced pluripotent stem cells; lncRNA long non-coding RNA; lncRNAs; ncRNA, non-coding RNA; non-coding RNA; pluripotency; super-enhancers; transcriptome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism
  • B-Lymphocytes / cytology
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Cellular Reprogramming* / genetics
  • Cluster Analysis
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Gene Expression Profiling
  • Genetic Loci
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Untranslated / metabolism
  • Transcriptome*


  • Antigens, CD19
  • RNA, Untranslated