title: Wnt-promoted Isl1 expression through a novel TCF/LEF1 binding site and H3K9 acetylation in early stages of cardiomyocyte differentiation of P19CL6 cells.
abstract: Islet 1 (ISL1), a marker of second heart field progenitors, plays a crucial role in cardiomyocyte differentiation and proliferation. However, little is known about transcriptional regulating mechanisms on Isl1 gene expression. Recent studies have demonstrated that Wnt/β-catenin signaling regulates Isl1 expression during heart development. However, the detailed mechanisms still remain unclear. In the present study performed during differentiation of P19CL6 into cardiomyocytes, we explored the underlying regulating mechanisms on Wnt/β-catenin-mediated Isl1 expression after we first confirmed that Wnt/β-catenin signaling promoted cardiomyocyte differentiation partly through Isl1 activation. We found a novel TCF/LEF1 binding site that was located 2300 bp upstream of the Isl1 ATG. Furthermore, Wnt/β-catenin signaling upregulated histone H3K9 acetylation on TCF/LEF1 binding sites on the Isl1 promoter, resulting in upregulation of Isl1 expression. This Wnt-mediated H3K9 acetylation on the Isl1 promoter was modulated by the acetyltransferase CREB-binding protein (CBP), instead of p300, through interaction with β-catenin. Collectively, these results suggest that in early stages of cardiomyocyte differentiation Wnt/β-catenin signaling promotes Isl1 expression via two ways: a novel TCF/LEF1 binding site and H3K9 acetylation conducted by CBP on the Isl1 promoter. To our knowledge, this is the first study reporting Wnt/β-catenin-regulated H3K9 acetylation on promoters of its target genes. And this study gives new insights into transcriptional regulating mechanisms of Wnt-mediated Isl1 expression during cardiomyocyte differentiation.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Huafei
authors.initials: H
authors.lastname: Lu
authors.forename: Yanming
authors.initials: Y
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yinan
authors.initials: Y
authors.lastname: Liu
authors.forename: Weiping
authors.initials: W
authors.lastname: Wang
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Jia
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Kangtao
authors.initials: K
authors.lastname: Ma
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006657:Histones / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D006657:Histones; D060850:LIM-Homeodomain Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C063843:insulin gene enhancer binding protein Isl-1; D050882:CREB-Binding Protein; D008239:Lysine