Epigenetic Variation Between Human Induced Pluripotent Stem Cell Lines Is an Indicator of Differentiation Capacity

Cell Stem Cell. 2016 Sep 1;19(3):341-54. doi: 10.1016/j.stem.2016.06.019. Epub 2016 Jul 28.

Abstract

Variation in the differentiation capacity of induced pluripotent stem cells (iPSCs) to specific lineages is a significant concern for their use in clinical applications and disease modeling. To identify factors that affect differentiation capacity, we performed integration analyses between hematopoietic differentiation performance and molecular signatures such as gene expression, DNA methylation, and chromatin status, using 35 human iPSC lines and four ESC lines. Our analyses revealed that hematopoietic commitment of PSCs to hematopoietic precursors correlates with IGF2 expression level, which in turn depends on signaling-dependent chromatin accessibility at mesendodermal genes. Maturation capacity for conversion of PSC-derived hematopoietic precursors to mature blood associates with the amount and pattern of DNA methylation acquired during reprogramming. Our study therefore provides insight into the molecular features that determine the differential capacities seen among human iPSC lines and, through the predictive potential of this information, highlights a way to select optimal iPSCs for clinical applications.

Keywords: DNA methylation; chromatin accessibility; hematopoietic differentiation; human induced pluripotent stem cell; insulin-like growth factor 2; mRNA microarray; reprogramming-related DNA methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Animals
  • Base Sequence
  • Cell Differentiation / genetics*
  • Cell Line
  • Cell Lineage / genetics
  • Cellular Reprogramming / genetics
  • Chromatin / chemistry
  • DNA Methylation / genetics
  • Epigenesis, Genetic*
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism
  • Fibroblast Growth Factors / metabolism
  • Gene Regulatory Networks
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Insulin-Like Growth Factor II / metabolism
  • Megakaryocytes / cytology
  • Megakaryocytes / metabolism
  • Mice, SCID
  • Signal Transduction / genetics
  • Stem Cell Transplantation
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism

Substances

  • Chromatin
  • Tripartite Motif Proteins
  • Activins
  • Fibroblast Growth Factors
  • Insulin-Like Growth Factor II