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Characterization of the circadian chromatin landscape using a novel CRISPR/Cas9-guided proximity-labelling technique

Project description

Mapping the body’s internal clock

Most living organisms have built-in clocks that synchronise with the seasons or the night and day cycle. The normal function of these 24-hour (or circadian) cycles is vital for humans, and continuing disruption of their rhythm results in serious illness. The actual process of circadian transmission is not well understood. The CLOCK project plans to use a CRISPR/Cas9-APEX labelling method (CASPEX) to map the three main circadian regulatory regions and to look for new clock modifiers. The outcome is expected to provide more understanding when treating the high incidence in the EU of pathologies linked to circadian rhythm disruption such as cancer, diabetes, and cardiovascular and neurodegenerative diseases.


To stay in synchrony with environmental cycles, most living organisms possess endogenous clocks. Circadian clocks are molecular oscillators present in most mammalian cells that drive circadian (~24 h) rhythms of a wide range of molecular, physiological and behavioral functions. Circadian clocks are essential for health. In humans their dysregulation (e.g. caused by shift work, jet lag etc.) has been associated with the development of multiple pathologies (e.g. cancer, metabolic diseases like diabetes and obesity as well as cardiovascular and neurodegenerative diseases) prevalent in the European Union.

One central aspect of molecular oscillator function is the tight regulation of circadian transcription. Over the years, several proteins and cis-regulatory enhancer elements (i.e. specific sequences located around the promoter region, e.g. E-box, RRE, D-box) have been shown to be essential for circadian transcription. However, mainly because of technical limitations, those studies focused on few regulators and have left many gaps in the understanding of the dynamics of the circadian transcription. Therefore, this project proposes to use state-of-the-art quantitative genomic-locus proteomics to provide the first comprehensive and unbiased characterization of the rhythmic protein binding at key circadian regulatory regions – a key regulatory node of circadian clock function Using a CRISPR/Cas9-APEX labelling method (CASPEX), we will first characterize the circadian chromatin landscape of the three main circadian regulatory regions (i.e. E-boxes, RREs, D-boxes). We expect to find new clock modifiers, whose role for circadian rhythm generation will be investigated in a subsequent part of the project, using an RNAi-based secondary screen. Overall, this project will provide novel insights in the circadian oscillator mechanism in humans, which is essential for developing better treatment strategies for circadian clock-associated disorders.


Net EU contribution
€ 162 806,40
Chariteplatz 1
10117 Berlin

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Berlin Berlin Berlin
Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00