title: cis-regulatory requirements for tissue-specific programs of the circadian clock.
abstract: BACKGROUND
  Broadly expressed transcriptions factors (TFs) control tissue-specific programs of gene expression through interactions with local TF networks. A prime example is the circadian clock: although the conserved TFs CLOCK (CLK) and CYCLE (CYC) control a transcriptional circuit throughout animal bodies, rhythms in behavior and physiology are generated tissue specifically. Yet, how CLK and CYC determine tissue-specific clock programs has remained unclear.
  
  
  RESULTS
  Here, we use a functional genomics approach to determine the cis-regulatory requirements for clock specificity. We first determine CLK and CYC genome-wide binding targets in heads and bodies by ChIP-seq and show that they have distinct DNA targets in the two tissue contexts. Computational dissection of CLK/CYC context-specific binding sites reveals sequence motifs for putative partner factors, which are predictive for individual binding sites. Among them, we show that the opa and GATA motifs, differentially enriched in head and body binding sites respectively, can be bound by OPA and SERPENT (SRP). They act synergistically with CLK/CYC in the Drosophila feedback loop, suggesting that they help to determine their direct targets and therefore orchestrate tissue-specific clock outputs. In addition, using in vivo transgenic assays, we validate that GATA motifs are required for proper tissue-specific gene expression in the adult fat body, midgut, and Malpighian tubules, revealing a cis-regulatory signature for enhancers of the peripheral circadian clock.
  
  
  CONCLUSIONS
  Our results reveal how universal clock circuits can regulate tissue-specific rhythms and, more generally, provide insights into the mechanism by which universal TFs can be modulated to drive tissue-specific programs of gene expression.
authors: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors: Antonio C A
authors: ACA
authors: Meireles-Filho
authors: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors: Anaïs F
authors: AF
authors: Bardet
authors: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors: J Omar
authors: JO
authors: Yáñez-Cuna
authors: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
authors: Gerald
authors: G
authors: Stampfel
authors: Research Institute of Molecular Pathology (IMP), 1030 Vienna, Austria. Electronic address: stark@starklab.org.
authors: Alexander
authors: A
authors: Stark
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D049750:Genome, Insect; D055106:Genome-Wide Association Study; D009928:Organ Specificity; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; D029721:Drosophila Proteins; C112805:cyc protein, Drosophila; D056926:CLOCK Proteins