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Investigation of genetic loci and molecular mechanisms important to the human circadian oscillator

English title Investigation of genetic loci and molecular mechanisms important to the human circadian oscillator
Applicant Brown Steven
Number 113874
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Genetics
Start/End 01.10.2006 - 30.09.2009
Approved amount 392'650.00
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All Disciplines (2)

Discipline
Genetics
Molecular Biology

Keywords (6)

human genetics; circadian rhythms; chronobiology; human behavior; gene expression; biochemistry

Lay Summary (English)

Lead
Lay summary
Human behavior is influenced by many genetic and environmental factors; it is therefore often difficult to study by reductionist approaches.However, in rare cases it can be linked directly to a biological process that can be understood at the cellular level. The circadian clock is one such instance: physiologically, it affects diverse processes such as sleep-wake time, activity patterns, body temperature, cardiac and respiratory rate, renal flow, and digestion. Molecularly, it is present in most cells of the body and modulates the transcription of about ten percent of our genes. As such, it presents an attractive model system both for understanding gene expression at a molecular level and for comprehending how gene regulation affects human behavior.

One major obstacle in studying the human circadian oscillator is the difficulty of measuring properties such as period length, a task so far achieved only by extensive subject observation under controlled conditions. We shall use a novel technique developed in our lab that allows the real-time recording of the period length of circadian gene expression in human fibroblasts derived from skin biopsies. In this granting period, I propose to conclude studies of circadian differences between old and young subjects, as well as to apply the method to new populations to study genetic differences between “morning” and “evening”individuals. (Extreme chronotypes from this study will provide the basis for a genetic linkage study at a later time to identify loci that specify human circadian behavior.) Finally, existing genetic pedigree banks of B cells will be screened for differences in circadian period, and the geneti c loci linked to these differences will be mapped.

To complement genetic approaches, our lab has also used biochemical methodologies to identify two new proteins important to circadian function, WDR5 and NONO. Both interact with the period family circadian proteins. While WDR5 is an adapter protein for a functionally well-characterized family of histone methylases, NONO has been found in a variety of contexts involving RNA transport and processing. Though NONO appears to be essential for circadian rhythms both in flies and in mammalian fibroblasts, its function herein is unknown. I shall take advantage of existing “genetrap” ES cell lines disrupting this X-linked gene, as well as fibroblast cell lines harboring tetracycline-inducible NONO siRNAs, to study the function of NONO in the circadian oscillator.Subsequent construction of a knockout mouse will permit the further analysis of the role that NONO plays both inside and outside the clock.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
126993 Molecular Mechanisms that Govern Human Daily Behavior 01.10.2009 Project funding
147111 Molecules and genes controlling diurnal behavior and physiology 01.04.2013 Project funding
147111 Molecules and genes controlling diurnal behavior and physiology 01.04.2013 Project funding

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