In this proposal we will use Drosophila as a model system to understand how circadian (E24 hr) systems adapt to seasonal changes in environmental conditions, with an emphasis on the relatively uncharacterized role of temperature. A major foundation is based on our long-standing work showing that in D. melanogaster the temperature-dependent splicing of the 3'-terminal intron (called dmpi8) from the critical clock component period (per) is a prominent """"""""thermosensor"""""""" that adjusts the distribution of daily wake-sleep cycles, eliciting seasonably appropriate responses. For example, on warm days splicing of the dmpi8 intron is inefficient leading to decreases in per RNA levels, events that prolong midday siesta and likely minimize the risks associated with desiccation during the hot midday hours. Recent progress indicates that multiple suboptimal splicing signals [i.e., 5'and 3'splice sites (ss)] are the basis for the thermosensitivity in the splicing efficiency of dmpi8, and endow D. melanogaster with the ability to prolong its midday siesta into the mid-to-late afternoon, presumably facilitating its adaptation to temperate climates where warm days are typically associated with extended periods of heat. Indeed, temperature-dependent changes in per 3'-terminal splicing efficiency and adjustments in daily wake-activity profiles are absent in several species of Drosophila that are naturally restricted to Afro- equatorial localities, wherein temperature and daylength undergo little fluctuation throughout the year. Consistent with our hypothesis, these non-thermal responsive species have strong 5'and 3'ss on their per 3'- terminal introns. Low temperatures likely stabilize the interaction of splicing factors with suboptimal splicing signals, providing a basis for thermal calibration. We will undertake a multi-faceted experimental strategy that includes biochemical, molecular, cell-culture and whole animal approaches to understand the cis- and trans- acting factors regulating the splicing efficiency of per 3'- terminal introns and how they modulate wake-sleep profiles in Drosophila. Newly identified natural polymorphisms in per that differentially regulate dmpi8 splicing and might vary geographically will be characterized. We will also determine whether the effects of dmpi8 splicing are preferentially mediated from the per-expressing morning or evening brain pacemaker centers and/or the more recently described arousal/sleep neurons. This analysis should provide further insights into our recent discovery that dmpi8 splicing regulates daytime sleep, suggesting novel non-circadian roles for per in modulating wake-sleep states. By undertaking comparative studies using a wide variety of natural populations and Drosophila species, this proposal offers a unique opportunity to integrate studies on gene expression and neural circuits controlling complex behaviors with ecological and evolutionary implications. On a broader perspective, our work suggests that natural selection operating at the level of splicing signals plays an important role in the thermal adaptation of life forms, raising broad implications for alternative splicing programs and transcriptome regulation, issues we will explore using massive-RNA sequencing technology.

Public Health Relevance

Like all animals, human's exhibit daily wake-sleep cycles that are controlled by a network of specialized cells called circadian clocks. The circadian system is not only involved in daily timing but also eliciting seasonably appropriate responses. This proposal will investigate how circadian clocks respond to seasonal changes in temperature, critical for the adaptation of life forms to temperate climates.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biological Rhythms and Sleep Study Section (BRS)
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Mitler, Merrill
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Zhang, Zhichao; Cao, Weihuan; Edery, Isaac (2018) The SR protein B52/SRp55 regulates splicing of the period thermosensitive intron and mid-day siesta in Drosophila. Sci Rep 8:1872
Yang, Yong; Edery, Isaac (2018) Parallel clinal variation in the mid-day siesta of Drosophila melanogaster implicates continent-specific targets of natural selection. PLoS Genet 14:e1007612
Cao, Weihuan; Edery, Isaac (2017) Mid-day siesta in natural populations of D. melanogaster from Africa exhibits an altitudinal cline and is regulated by splicing of a thermosensitive intron in the period clock gene. BMC Evol Biol 17:32
Lee, Jung-Eun; Rayyan, Morsi; Liao, Allison et al. (2017) Acute Dietary Restriction Acts via TOR, PP2A, and Myc Signaling to Boost Innate Immunity in Drosophila. Cell Rep 20:479-490
Cao, Weihuan; Edery, Isaac (2015) A novel pathway for sensory-mediated arousal involves splicing of an intron in the period clock gene. Sleep 38:41-51
Low, Kwang Huei; Chen, Wen-Feng; Yildirim, Evrim et al. (2012) Natural variation in the Drosophila melanogaster clock gene period modulates splicing of its 3'-terminal intron and mid-day siesta. PLoS One 7:e49536
Kim, Eun Young; Jeong, Eun Hee; Park, Sujin et al. (2012) A role for O-GlcNAcylation in setting circadian clock speed. Genes Dev 26:490-502
Edery, Isaac (2011) A master CLOCK hard at work brings rhythm to the transcriptome. Genes Dev 25:2321-6
Low, Kwang Huei; Lim, Cecilia; Ko, Hyuk Wan et al. (2008) Natural variation in the splice site strength of a clock gene and species-specific thermal adaptation. Neuron 60:1054-67
Chen, Wen-Feng; Majercak, John; Edery, Isaac (2006) Clock-gated photic stimulation of timeless expression at cold temperatures and seasonal adaptation in Drosophila. J Biol Rhythms 21:256-71

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