title: Cis-regulatory architecture of a brain signaling center predates the origin of chordates.
abstract: Genomic approaches have predicted hundreds of thousands of tissue-specific cis-regulatory sequences, but the determinants critical to their function and evolutionary history are mostly unknown. Here we systematically decode a set of brain enhancers active in the zona limitans intrathalamica (zli), a signaling center essential for vertebrate forebrain development via the secreted morphogen Sonic hedgehog (Shh). We apply a de novo motif analysis tool to identify six position-independent sequence motifs together with their cognate transcription factors that are essential for zli enhancer activity and Shh expression in the mouse embryo. Using knowledge of this regulatory lexicon, we discover new Shh zli enhancers in mice and a functionally equivalent element in hemichordates, indicating an ancient origin of the Shh zli regulatory network that predates the chordate phylum. These findings support a strategy for delineating functionally conserved enhancers in the absence of overt sequence homologies and over extensive evolutionary distances.
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Hopkins Marine Station, Department of Biology, Stanford University, Pacific Grove, California, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Minor
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ying-Tao
authors.initials: YT
authors.lastname: Zhao
authors.affiliation: Department of Genetic Engineering, College of Life Sciences and Graduate School of Biotechnology, Kyung Hee University, Yongin-si, Republic of Korea.
authors.forename: Yongsu
authors.initials: Y
authors.lastname: Jeong
authors.affiliation: Hopkins Marine Station, Department of Biology, Stanford University, Pacific Grove, California, USA.
authors.forename: Ariel M
authors.initials: AM
authors.lastname: Pani
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Anna N
authors.initials: AN
authors.lastname: King
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Symmons
authors.affiliation: Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.affiliation: Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, New York, USA.
authors.forename: Wellington V
authors.initials: WV
authors.lastname: Cardoso
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: François
authors.initials: F
authors.lastname: Spitz
authors.affiliation: Hopkins Marine Station, Department of Biology, Stanford University, Pacific Grove, California, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lowe
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Epstein
mesh_terms: D000818:Animals; D043344:Chordata / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D014157:Transcription Factors