title: Brachyury, Foxa2 and the cis-Regulatory Origins of the Notochord.
abstract: A main challenge of modern biology is to understand how specific constellations of genes are activated to differentiate cells and give rise to distinct tissues. This study focuses on elucidating how gene expression is initiated in the notochord, an axial structure that provides support and patterning signals to embryos of humans and all other chordates. Although numerous notochord genes have been identified, the regulatory DNAs that orchestrate development and propel evolution of this structure by eliciting notochord gene expression remain mostly uncharted, and the information on their configuration and recurrence is still quite fragmentary. Here we used the simple chordate Ciona for a systematic analysis of notochord cis-regulatory modules (CRMs), and investigated their composition, architectural constraints, predictive ability and evolutionary conservation. We found that most Ciona notochord CRMs relied upon variable combinations of binding sites for the transcription factors Brachyury and/or Foxa2, which can act either synergistically or independently from one another. Notably, one of these CRMs contains a Brachyury binding site juxtaposed to an (AC) microsatellite, an unusual arrangement also found in Brachyury-bound regulatory regions in mouse. In contrast, different subsets of CRMs relied upon binding sites for transcription factors of widely diverse families. Surprisingly, we found that neither intra-genomic nor interspecific conservation of binding sites were reliably predictive hallmarks of notochord CRMs. We propose that rather than obeying a rigid sequence-based cis-regulatory code, most notochord CRMs are rather unique. Yet, this study uncovered essential elements recurrently used by divergent chordates as basic building blocks for notochord CRMs.
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Diana S
authors.initials: DS
authors.lastname: José-Edwards
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Izumi
authors.initials: I
authors.lastname: Oda-Ishii
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Kugler
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Yale J
authors.initials: YJ
authors.lastname: Passamaneck
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Katikala
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nibu
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Gregorio
mesh_terms: D000818:Animals; D001665:Binding Sites; D019521:Body Patterning / Q000235:genetics; D002938:Ciona intestinalis / Q000235:genetics / Q000254:growth & development; D005326:Fetal Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics*; D051379:Mice; D009672:Notochord / Q000254:growth & development*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000235:genetics*; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein