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ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif
Dept. of Mol. Pathol., Graduate School of Medicine, Univ. of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Dept. of Mol. Pathol., Graduate School of Medicine, Univ. of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Genome Science Div., Res. Center for Adv. Science and Technol., Univ. of Tokyo, Meguro-ku, Tokyo 153-8904, Japan.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
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2011 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 20, 8712-8727 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press , 2011. Vol. 39, no 20, 8712-8727 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-160812DOI: 10.1093/nar/gkr572ISI: 000296343400014PubMedID: 21764776OAI: oai:DiVA.org:uu-160812DiVA: diva2:453092
Available from: 2011-11-01 Created: 2011-11-01 Last updated: 2012-03-14Bibliographically approved

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Vasilaki, EleftheriaHeldin, Carl-HenrikMiyazono, Kohei
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