title: ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif.
abstract: Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) and pulmonary arterial smooth muscle cells (PASMCs) are implicated in human genetic disorders. Here, we generated genome-wide maps of Smad1/5 binding sites in ECs and PASMCs. Smad1/5 preferentially bound to the region outside the promoter of known genes, and the binding was associated with target gene upregulation. Cell-selective Smad1/5 binding patterns appear to be determined mostly by cell-specific differences in baseline chromatin accessibility patterns. We identified, for the first time, a Smad1/5 binding motif in mammals, and termed GC-rich Smad binding element (GC-SBE). Several sequences in the identified GC-SBE motif had relatively weak affinity for Smad binding, and were enriched in cell type-specific Smad1/5 binding regions. We also found that both GC-SBE and the canonical SBE affect binding affinity for the Smad complex. Furthermore, we characterized EC-specific Smad1/5 target genes and found that several Notch signaling pathway-related genes were induced by BMP in ECs. Among them, a Notch ligand, JAG1 was regulated directly by Smad1/5, transactivating Notch signaling in the neighboring cells. These results provide insights into the molecular mechanism of BMP signaling and the pathogenesis of vascular lesions of certain genetic disorders, including hereditary hemorrhagic telangiectasia.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Morikawa
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Vasilaki
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Kanki
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000235:genetics; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D015894:Genome, Human; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059372:Nucleotide Motifs; D011651:Pulmonary Artery / Q000166:cytology; D051880:Receptors, Notch / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D017422:Sequence Analysis, DNA; D000072099:Serrate-Jagged Proteins; D051898:Smad1 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein