The role of DOMINO in regulation of circadian rhythms in Drosophila
Most organisms on earth use circadian clocks to modulate their bodily functions, thus adapting their metabolism, physiology and behavior to these daily environmental cycles. Malfunctions of circadian clocks are correlated with many human diseases. For example, disrupted circadian rhythms in shift workers are thought to increase the prevalence of cancers, cardiovascular diseases, diabetes and other metabolic diseases. Circadian clocks control rhythmic expression of around 10-15% of mammalian transcripts. The fruit fly Drosophila melanogaster is an excellent model to study circadian clock because of its well-characterized genome, powerful genetics tools, and high throughput automated behavioral assays. In addition, the core of the circadian pacemaker is highly conserved among species, and the molecular mechanisms of circadian clocks were, in great part, discovered in Drosophila. Studying circadian rhythms in Drosophila has profound significance in basic biology and for human health. I have uncovered a novel regulator of Drosophila circadian function for maintaining the locomotor rhythms. This gene is called domino (dom), an important chromatin remodeling protein. DOM plays a critical role in transcriptional regulation by replacing the histone H2A with the H2A.V variant (6). An exchanges of the H2A variant with the H2A affects nucleosome mobility and positioning, thus regulating transcription. We will: 1) define the role of DOM in the control of Drosophila circadian rhythms and sleep. 2) elucidate the mechanism of DOM in the control of circadian rhythms; and 3) identify the protein partners and targets of DOM in circadian neurons. These studies will reveal a novel mechanism of the circadian clock by chromatin remodeling and will advance our understanding of circadian clocks. Chromatin remodeling mechanisms are involved in many metabolic diseases and cancer, which are known to be associated with disruption of circadian clocks. These studies will ultimately lead to improvement of therapeutic methods for circadian clock related diseases.