bZIP Protein Function in an Organismal Model for Peripheral Circadian Clocks

University Of North Carolina Charlotte, Charlotte NC

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Abstract

? DESCRIPTION (provided by applicant): The major objective of this Academic Research Enhancement Award (AREA) R15 proposal is to determine the function of proline and acidic amino acid-rich basic leucine zipper (PAR-bZIP) transcription factors in the circadian clock of a model invertebrate as an organismal model for mammalian peripheral clocks. In mammals and many multicellular organisms, organs and tissues comprise a hierarchically structured circadian network where central regulators, like the suprachiasmatic nucleus (SCN), regulate the internal clock and signal peripheral clocks to synchronize outputs. The desynchronization of peripheral clocks due either to improper regulation of the SCN or competing signaling between the SCN and environmental cues may provide a mechanism resulting in neurological and physiological conditions, including increased risk for metabolic disorders and cancer. Our published and preliminary data have shown the circadian clock of the cnidarian Nematostella vectensis has oscillating gene expression for conserved circadian clock components that are largely shared with mammals and insects. However, behavioral and gene expression data support a hypothesis that the anemone clock requires continued environmental entrainment suggesting it functions akin to a peripheral clock in mammals without a central pacemaker. Thus, we propose to utilize this species as an organismal model to characterize the molecular mechanisms in oscillations and loss of synchronization of peripheral clocks. To understand the roles of PAR-bZIPs in function of peripheral clocks, we will characterize the reciprocal interactions of these proteins and the bHLH-PAS transcription factor Clock for regulating expression (Aim 1), DNA binding specificity of PAR-bZIPs using unbiased oligo microarrays and identification of regulated genes via genome mapping (Aim 2), and shifts and loss of oscillating gene expression by PAR-bZIPs after removal of an entraining cue (Aim 3). Together, the proposed research will test the role of PAR-bZIP proteins as central contributors to the cnidarian circadian clock and further establish this invertebrate species as an experimental model for understanding the mechanisms of peripheral clocks.