Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming

Cell Stem Cell. 2010 Jul 2;7(1):64-77. doi: 10.1016/j.stem.2010.04.015. Epub 2010 Jun 17.

Abstract

Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by expression of defined embryonic factors. However, little is known of the molecular mechanisms underlying the reprogramming process. Here we explore somatic cell reprogramming by exploiting a secondary mouse embryonic fibroblast model that forms iPSCs with high efficiency upon inducible expression of Oct4, Klf4, c-Myc, and Sox2. Temporal analysis of gene expression revealed that reprogramming is a multistep process that is characterized by initiation, maturation, and stabilization phases. Functional analysis by systematic RNAi screening further uncovered a key role for BMP signaling and the induction of mesenchymal-to-epithelial transition (MET) during the initiation phase. We show that this is linked to BMP-dependent induction of miR-205 and the miR-200 family of microRNAs that are key regulators of MET. These studies thus define a multistep mechanism that incorporates a BMP-miRNA-MET axis during somatic cell reprogramming. PAPERCLIP:

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Cellular Reprogramming / genetics
  • Cellular Reprogramming / physiology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Flow Cytometry
  • Genomics / methods*
  • Immunoblotting
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mesoderm / metabolism
  • Mesoderm / pathology*
  • Models, Biological
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism

Substances

  • Bone Morphogenetic Proteins
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Myc protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse

Associated data

  • GEO/GSE21757