Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis


  • E. Karantzali
  • H. Schulz
  • O. Hummel
  • N. Huebner
  • A. Hatzopoulos
  • A. Kretsovali


  • Genome Biology


  • Genome Biol 9 (4): R65


  • BACKGROUND: Epigenetic mechanisms regulate gene expression patterns affecting cell function and differentiation. In this report, we examine the role of histone acetylation in gene expression regulation in mouse embryonic stem cells employing a transcriptomic and epigenetic analysis. RESULTS: Embryonic stem cells treated with the histone deacetylase inhibitor Trichostatin A (TSA), undergo morphological and gene expression changes indicative of differentiation. Gene profiling utilizing Affymetrix microarrays revealed the suppression of important pluripotency factors, including Nanog, a master regulator of stem cell identity, and the activation of differentiation-related genes. Transcriptional and epigenetic changes induced after 6 to 12 hours of TSA treatment mimic those that appear during embryoid body differentiation. We show here that the early steps of stem cell differentiation are marked by the enhancement of bulk activatory histone modifications. At the individual gene level, we found that transcriptional reprogramming triggered by histone deacetylase inhibition correlates with rapid changes of the activating K4 and the repressive K27 trimethylations of histone H3. The establishment of H3K27 trimethylation is required for stable gene suppression whereas in its absence, genes can be reactivated upon TSA removal. CONCLUSION: Our data suggest that inhibition of histone deacetylases accelerates the early events of differentiation, by regulating the expression of pluripotency- and differentiation-associated genes in an opposite manner. This analysis provides information about genes that are important for ES cell function and the epigenetic mechanisms that regulate their expression.