Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells.
Histone deacetylases (HDACs) have a central role in the regulation of gene expression. Here we investigated whether HDAC7 has an impact on embryonic stem (ES) cell differentiation into smooth muscle cells (SMCs). ES cells were seeded on collagen-IV-coated flasks and cultured in the absence of leukemia inhibitory factor in differentiation medium to induce SMC differentiation. Western blots and double-immunofluorescence staining demonstrated that HDAC7 has a parallel expression pattern with SMC marker genes. In ex vivo culture of embryonic cells from SM22-LacZ transgenic mice, overexpression of HDAC7 significantly increased beta-galactosidase-positive cell numbers and enzyme activity, indicating its crucial role in SMC differentiation during embryonic development. We found that HDAC7 undergoes alternative splicing during ES cell differentiation. Platelet-derived growth factor enhanced ES cell differentiation into SMCs through upregulation of HDAC7 splicing. Further experiments revealed that HDAC7 splicing induced SMC differentiation through modulation of the SRF-myocardin complex. These findings suggest that HDAC7 splicing is important for SMC differentiation and vessel formation in embryonic development.
Margariti
Andriana
A
Cardiovascular Division, King's College London BHF Centre, London SE5 9NU, UK.
Xiao
Qingzhong
Q
Zampetaki
Anna
A
Zhang
Zhongyi
Z
Li
Hongling
H
Martin
Daniel
D
Hu
Yanhua
Y
Zeng
Lingfang
L
Xu
Qingbo
Q
D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D000077214:Becaplermin; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D064326:MEF2 Transcription Factors; D051379:Mice; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D000099251:Myocardin
D000077214:Becaplermin; D004247:DNA; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D011494:Protein Kinases; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099251:Myocardin; C578041:Mef2c protein, mouse; C405628:serum response factor kinase; C543274:Hdac7 protein, mouse