Published online before print February 10, 2005, doi: 10.1161/01.RES.0000159181.06379.63
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© 2005 American Heart Association, Inc.
Molecular Medicine |
Epigenetic Histone Modification and Cardiovascular Lineage Programming in Mouse Embryonic Stem Cells Exposed to Laminar Shear Stress
From the Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Fondazione "I. Monzino" IRCCS (B.I., P.B.), Milan, Italy; Laboratorio di Patologia Vascolare (A.S., L.M., M.C.C., C.G.), Istituto Dermopatico dell’Immacolata, IRCCS, Rome, Italy; Laboratorio di Oncogenesi Molecolare (S.N., A.F.), Istituto Regina Elena, Rome, Italy; and Istituto di Neurobiologia e Medicina Molecolare, CNR, Rome, Italy.
Correspondence to Carlo Gaetano, MD, Laboratorio di Patologia Vascolare, IDI-IRCCS, Via dei Monti di Creta 104, 00167, Rome Italy. E-mail gaetano{at}idi.it
Experimental evidence indicates that shear stress (SS) exerts a morphogenetic function during cardiac development of mouse and zebrafish embryos. However, the molecular basis for this effect is still elusive. Our previous work described that in adult endothelial cells, SS regulates gene expression by inducing epigenetic modification of histones and activation of transcription complexes bearing acetyltransferase activity. In this study, we evaluated whether SS treatment could epigenetically modify histones and influence cell differentiation in mouse embryonic stem (ES) cells. Cells were exposed to a laminar SS of 10 dyne per cm2/s–1, or kept in static conditions in the presence or absence of the histone deacetylase inhibitor trichostatin A (TSA). These experiments revealed that SS enhanced lysine acetylation of histone H3 at position 14 (K14), as well as serine phosphorylation at position 10 (S10) and lysine methylation at position 79 (K79), and cooperated with TSA, inducing acetylation of histone H4 and phosphoacetylation of S10 and K14 of histone H3. In addition, ES cells exposed to SS strongly activated transcription from the vascular endothelial growth factor (VEGF) receptor 2 promoter. This effect was paralleled by an early induction of cardiovascular markers, including smooth muscle actin, smooth muscle protein 22-
, platelet-endothelial cell adhesion molecule-1, VEGF receptor 2, myocyte enhancer factor-2C (MEF2C), and -sarcomeric actin. In this condition, transcription factors MEF2C and Sma/MAD homolog protein 4 could be isolated from SS-treated ES cells complexed with the cAMP response element-binding protein acetyltransferase. These results provide molecular basis for the SS-dependent cardiovascular commitment of mouse ES cells and suggest that laminar flow may be successfully applied for the in vitro production of cardiovascular precursors.
Key Words: shear stress • flow • embryonic stem cell • chromatin • differentiation
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