Dynamic changes in histone H3 phosphoacetylation during early embryonic stem cell differentiation are directly mediated by mitogen- and stress-activated protein kinase 1 via activation of MAPK pathways.
Embryonic stem (ES) cells are pluripotent cells capable of unlimited self-renewal and differentiation into the three embryonic germ layers under appropriate conditions. Mechanisms for control of the early period of differentiation, involving exit from the pluripotent state and lineage commitment, are not well understood. An emerging concept is that epigenetic histone modifications may play a role during this early period. We have found that upon differentiation of mouse ES cells by removal of the cytokine leukemia inhibitory factor, there is a global increase in coupled histone H3 phosphorylation (Ser-10)-acetylation (Lys-14) (H3 phosphoacetylation). We show that this occurs through activation of both the extracellular signal-regulated kinase (ERK) and p38 MAPK signaling pathways. Early ES cell differentiation is delayed using pharmacological inhibitors of the ERK and p38 pathways. One common point of convergence of these pathways is the activation of the mitogen- and stress-activated protein kinase 1 (MSK1). We show here that MSK1 is the critical mediator of differentiation-induced H3 phosphoacetylation using both the chemical inhibitor H89 and RNA interference. Interestingly, inhibition of H3 phosphoacetylation also alters gene expression during early differentiation. These results point to an important role for both epigenetic histone modifications and kinase pathways in modulating early ES differentiation.
Lee
Elliot R
ER
Cancer Biology Graduate Program, University of Wisconsin, Madison, Wisconsin 53706.
McCool
Kevin W
KW
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706.
Murdoch
Fern E
FE
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706.
Fritsch
Michael K
MK
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706. Electronic address: mkfritsch@wisc.edu.
D000818:Animals; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D006657:Histones; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases