Cis-regulatory architecture of a brain signaling center predates the origin of chordates

Yao Yao, Paul J. Minor, Ying Tao Zhao, Yongsu Jeong, Ariel M. Pani, Anna N. King, Orsolya Symmons, Lin Gan, Wellington V. Cardoso, Fran'ois Spitz, Christopher J. Lowe, Douglas J. Epstein

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)575-580
Number of pages6
JournalNature Genetics
Issue number5
StatePublished - May 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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