The cold-responsive circadian gene regulatory landscape and its relevance to torpor

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This project aims to understand the molecular mechanisms by which cold temperatures regulate genes and behaviour. In response to severe environmental conditions such as cold temperatures during winter or at times of food shortage, many mammals adopt a remarkable behaviour known as torpor. Here, animals enter a state of reduced metabolism, and this is accompanied by a drastic drop in their body temperature. A series of prolonged bouts of torpor is referred to as hibernation. Despite the importance of torpor to animal biology, to date, we do not understand the molecular mechanisms that control the entry, maintenance, and exit from this state, but such knowledge would provide the substrate for paradigm-shifting advances in emergency medicine, longevity, and space travel. We have recently identified links between cooling and the circadian clock that may explain some of the most fundamental aspects of torpor. The circadian clock is an ancient highly conserved time keeping mechanism inherent to all life. The circadian clock aligns almost all aspects of cellular and organism physiology to the earth's 24h day and night cycle. The ability to adjust the clock to a changing environment is of fundamental importance to health and most of us have experienced the consequences of a mal-adjusted clock in the form of "jetlag". Temperature is a crucial time cue to the circadian clock, and how this signal is interpreted to impact on clock genes is largely unknown.We discovered that cooling human heart cells to low temperatures, as experienced by patients during surgical procedures, has a profound impact on the architecture of the chromosomes. This results in the dramatic activation of genes that negatively regulate the circadian clock and thus stop or "freeze" its rhythmicity. Rewarming cells reactivates rhythmicity and effectively causes the resetting of the clock. There are remarkable similarities between these observations we made in the human cell model and torpor in small mammals. The same genes are activated when animals enter torpor and resetting of the circadian clock has been proposed to be critical for the exit from torpor. These parallels offer a unique opportunity to address the fundamental mechanisms that control both circadian rhythms and torpor.Our cooling and rewarming approach using cultured human cells provides us with a simple but effective controllable procedure to unravel the molecular mechanisms that change the structure of chromosomes and thus activate and deactivate clock genes. In this proposal we will use the very latest biochemical and microscopy approaches to characterise the changes to the architecture of the chromosomes at unprecedented resolution and elucidate how this regulates and resets the cellular clock. We can then use the same methodology to understand how these mechanisms also govern and reconfigure the cells of mice in torpor. Defining the role that the reconfiguration of chromosomal architecture plays in the regulation of the cellular clock is fundamental to the understanding of the mechanics that underpin cellular time keeping, and its role in biological processes such as in torpor. Whilst we cannot enter torpor, understanding of these mechanisms may provide strategies to induce torpor like states in humans. This would open tremendous new applications in medicine in particular for the treatment of trauma patients to prevent tissue damage and may help to prologue the storage of transplant organs. In addition, torpor as a tool would provide solutions to many challenges including muscle and bone loss, and radiation exposure that have to be overcome to enable humans to survive long duration space travel.