Pluripotency associated genes are reactivated by chromatin-modifying agents in neurosphere cells

Stem Cells. 2008 Apr;26(4):920-6. doi: 10.1634/stemcells.2007-0649. Epub 2008 Jan 17.

Abstract

Chromatin architecture in stem cells determines the pattern of gene expression and thereby cell identity and fate. The chromatin-modifying agents trichostatin A (TSA) and 5-Aza-2'-deoxycytidine (AzaC) affect histone acetylation and DNA methylation, respectively, and thereby influence chromatin structure and gene expression. In our previous work, we demonstrated that TSA/AzaC treatment of neurosphere cells induces hematopoietic activity in vivo that is long-term, multilineage, and transplantable. Here, we have analyzed the TSA/AzaC-induced changes in gene expression by global gene expression profiling. TSA/AzaC caused both up- and downregulation of genes, without increasing the total number of expressed genes. Chromosome analysis showed no hot spot of TSA/AzaC impact on a particular chromosome or chromosomal region. Hierarchical cluster analysis revealed common gene expression patterns among neurosphere cells treated with TSA/AzaC, embryonic stem (ES) cells, and hematopoietic stem cells. Furthermore, our analysis identified several stem cell genes and pluripotency-associated genes that are induced by TSA/AzaC in neurosphere cells, including Cd34, Cd133, Oct4, Nanog, Klf4, Bex1, and the Dppa family members Dppa2, 3, 4, and 5. Sox2 and c-Myc are constitutively expressed in neurosphere cells. We propose a model in which TSA/AzaC, by removal of epigenetic inhibition, induces the reactivation of several stem cell and pluripotency-associated genes, and their coordinate expression enlarges the differentiation potential of somatic precursor cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / drug effects
  • Pluripotent Stem Cells / physiology*
  • Prosencephalon / cytology
  • Prosencephalon / drug effects
  • Prosencephalon / physiology

Substances

  • Chromatin
  • Hydroxamic Acids
  • trichostatin A