Dr. Young studies circadian clocks, which are endogenous mechanisms that time the recurring, daily activities observed in most organisms. Young's research has shown how interactions among certain genes and their proteins produce molecular oscillations at the level of individual cells. These cellular clocks are active in most animal tissues and establish overt, circadian rhythms in physiology and behavior. His lab’s findings have implications for sleep and mood disorders as well as dysfunctions related to the timing of gene activities underlying visual functions, locomotion, metabolism, immunity, learning and memory.
Studies of the molecular basis for circadian rhythmicity began in the early 1980s in Young’s laboratory at Rockefeller, and in the laboratories of Jeffrey Hall and Michael Rosbash at Brandeis University. Over the past 30 years the work of these investigators, which focused on the fruitfly Drosophila melanogaster, has shown that the fly’s circadian clocks are formed through the actions of a small group of genes including per (period), tim (timeless), dbt (double-time, casein kinase 1), clk (clock), cyc (cycle), sgg(shaggy), Pdp1 (PAR domain protein 1), vri (vrille), cry (cryptochrome) and ck2 (casein kinase 2). Six of these genes were first characterized in the Young laboratory, and mutations in any of these “clock” genes can lengthen or shorten the period of behavioral, physiological and molecular circadian rhythms, or can abolish the rhythms altogether.
The abundance of per, tim, vri, Pdp1 and clk RNA and their encoded proteins changes rhythmically with a circadian period in wild-type flies. In addition to these RNA and protein rhythms, two of the proteins, TIM and PER, rhythmically shift their sub-cellular location. Young and his colleagues found that these two proteins accumulate, pair up in the cell’s cytoplasm and then migrate into the nucleus, where their presence switches off their production by shutting down the per and tim genes. However, these events are timed so that PER and TIM are retained in the cytoplasm for a fixed interval of several hours. This delay promotes RNA and protein rhythms and determines the period of the clock.
The circadian clock adjusts to environmental photo-cycles through the activities of CRY and TIM. The former protein is a novel photoreceptor that binds to TIM in the presence of light and promotes TIM’s rapid degradation, pausing the clock until TIM can re-accumulate in the dark. Young’s laboratory also discovered that the enzyme casein kinase 1 (DBT) further regulates the pace of this 24-hour molecular clock by restricting the longevity of the PER protein during each circadian cycle, and especially by removing PER at times when TIM is absent. Others have recently shown that faulty interactions between casein kinase 1 and PER are responsible for certain heritable sleep disorders in humans. In fact, most of the genes composing the Drosophila clock, and the cycling intracellular mechanism they direct, are well conserved throughout the animal kingdom.
The Young laboratory has used oligonucleotide microarrays that represent all 14,000 fly genes to study the gene expression programs regulated by the circadian clock. They have found that in the Drosophila head, approximately 400 to 500 genes — about six to seven percent of all genes active in the head — are expressed with a circadian rhythm. Genes composing this large circadian program influence almost every aspect of the fly’s biology, and subsets of these genes are switched on and off with phases representing every hour of the day and night. When genes that compose the circadian clock are mutated, this program of temporally sequenced gene expression disappears even if environmental cycles are present, indicating that the temporal program is thoroughly dependent on the molecular oscillator.
Recently members of the Young laboratory have identified genes that affect the homeostatic regulation of sleep in Drosophila. This research has uncovered specific neurons whose activity promotes sleep. They have also begun to study sleep and circadian rhythms at the genetic and molecular levels in humans. The latter work involves collaborative studies of circadian behavioral and physiological rhythms that are coupled to studies in the Young laboratory that assess rhythmic gene and protein activities established in cultured cells derived from patients with certain sleep and depressive disorders.