title: Conversion of MyoD to a neurogenic factor: binding site specificity determines lineage.
abstract: MyoD and NeuroD2, master regulators of myogenesis and neurogenesis, bind to a "shared" E-box sequence (CAGCTG) and a "private" sequence (CAGGTG or CAGATG, respectively). To determine whether private-site recognition is sufficient to confer lineage specification, we generated a MyoD mutant with the DNA-binding specificity of NeuroD2. This chimeric mutant gained binding to NeuroD2 private sites but maintained binding to a subset of MyoD-specific sites, activating part of both the muscle and neuronal programs. Sequence analysis revealed an enrichment for PBX/MEIS motifs at the subset of MyoD-specific sites bound by the chimera, and point mutations that prevent MyoD interaction with PBX/MEIS converted the chimera to a pure neurogenic factor. Therefore, redirecting MyoD binding from MyoD private sites to NeuroD2 private sites, despite preserved binding to the MyoD/NeuroD2 shared sites, is sufficient to change MyoD from a master regulator of myogenesis to a master regulator of neurogenesis.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Pediatrics, Division of Hematology-Oncology, University of Washington School of Medicine, Seattle, WA 98105, USA. Electronic address: apfong@fhcrc.org.
authors: Abraham P
authors: AP
authors: Fong
authors: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Zizhen
authors: Z
authors: Yao
authors: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Jun Wen
authors: JW
authors: Zhong
authors: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Nathan M
authors: NM
authors: Johnson
authors: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Gist H
authors: GH
authors: Farr
authors: Department of Pediatrics, Division of Cardiology, University of Washington, Seattle, WA 98105, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors: Lisa
authors: L
authors: Maves
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA 98105, USA. Electronic address: stapscot@fhcrc.org.
authors: Stephen J
authors: SJ
authors: Tapscott
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D024721:E-Box Elements / Q000235:genetics*; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D017570:MyoD Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein