Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis.
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 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 6-12 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 in activating K4 trimethylation and repressive K27 trimethylation 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.


CONCLUSIONS
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 embryonic stem cell function and the epigenetic mechanisms that regulate their expression.
Karantzali
Efthimia
E
Institute of Molecular Biology and Biotehnology, FORTH, Heraklion 71110 Greece.
Schulz
Herbert
H
Hummel
Oliver
O
Hubner
Norbert
N
Hatzopoulos
Ak
A
Kretsovali
Androniki
A
D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000166:cytology*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A