Preethi Gunaratne

Linking Circadian Rhythm and Satiety Through Non-Coding RNAs and Epigenetic Mechanisms

Obesity and anorexia (chronic self-starvation behavior) are major public health problems that result from the disruption of pathways that regulate body-weight and adiposity in response to environmental cues. Leptin a protein expressed exclusively in adipose tissue by the Ob gene in mouse is the central regulator and ‘thermostat’ of fat stores in the body. The level of leptin reflects the available triglyceride stores in adipose tissue and acts through a feed-back control mechanism to induce caloric restriction when the levels are high and feeding when the levels are low. Feeding has been linked to the sleep-wake cycle although the mechanisms underlying this link remain elusive. Leptin for instance has been well established to exhibit striking circadian rhythm with the peak occurring in the sleep-phase of the sleep-wake cycle in humans. Furthermore, Prader-Willi Syndrome (PWS) patients exhibit compulsive eating behavior mainly at night.

Our Hypothesis is That Non-Coding RNAs and Epigenetic Factors Play a Central Role in Linking Circadian Rhythm and Satiety in Mammals

This is based on two key observations made in our laboratory. First, we have identified microRNAs that exhibit circadian rhythm of expression in the liver and SCN (controls the central biological clock in mammals) that have predicted binding sites in the 3’-untranslated region (3’-UTR) of both clock genes (Per1, Per2, Per3 and Cry2) as well as a number of genes implicated in hyperphagia, satiety and obesity. The second line of evidence comes from In situ hybridization experiments on brain slices from mouse which revealed that these miRNAs are co-expressed with their predicted targets both in the SCN (master regulator of circadian genes) and PVN (master regulator of satiety). MicroRNAs (miRNAs) are small (~22 nt) non-coding RNAs that bind sequences in the 3’-untranslated region (3’-UTRs) of protein coding genes to repress expression through mRNA decay and/or translational repression. The RNase III-Dicer is essential for the biogenesis of miRNAs. We have preliminary evidence that homozygous Dicer null mutants in embryonic stem cells (ES [Dicer-/-]) exhibit significant changes in the epigenome [Histone 3 Lysine 9 di-methylation (H3K9me2)] patterns at two non-coding snoRNA clusters (MBII-52 and MBII-85) in the imprinted Prader-Will Syndrome (PWS) region. MBII-52 snoRNA cluster has been well established to be essential for guiding proper splicing of HTR2c. The MBII-85 snoRNA cluster has been postulated to be the minimum critical region for PWS. Collectively these datasets make a compelling argument for a central role for Dicer-dependent non-coding RNAs and epigenetic marks in the integration of circadian rhythm and satiety pathways in mammals. Based on these findings we are carrying out genome-wide studies on non-coding RNA expression and epigenetic changes in the SCN and PVN through the circadian cycle and in mouse models of obesity.

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