In the rhythm of DNA

The world around us is surprisingly predictable. Most of flowers bloom in the spring, birds migrate in the autumn and humans wake up similar time every day. Our and most of other living organisms bodies have an inner rhythm and if certain behaviours repeat every 24 hours we often call it circadian rhythm. Circadian rhythm is a biological process of endogenous and entrainable (named this way if certain event matches its period with that of an environment) oscillation. There are various examples in world of living organisms: cyanobacteria alternate photosynthesis and nitrogen fixation, plants regulate the leaves movements and human show sleep-wake or hunger cycles. In our organism primary circadian clock is located in suprachiasmatic nucleus (SCN) and receives information about illumination from retina in the eye. After interpretation of received data SCN passes it on the pineal gland which secretes melatonin – hormone which provides information about the length of the night. This is one of the key events regulating the circadian physiology or behaviour in humans.

Beside the “master clock” more or less independent circadian oscillations also exist in many organs in our body – like liver, muscles or kidneys. However the most exciting part of circadian regulations happens on the cellular level – the key regulatory component of the oscillations. Circadian rhythms have genetic basis. The system relies on the positive and negative auto-regulatory feedback loops of transcription and translation. In mammals the core of primary circadian clock machinery is determined by activity of CLOCK and BMAL1 heterodimer which initiates transcription of negative regulators PER and CRY. After translation in the cytoplasm PER:CRY complexes translocate back to the nucleus and inhibit activity of CLOCK:BMAL1 heterodimer, repressing their own transcription that way. This process drives rhythmical activity of many other proteins in the nucleolus and allows the circadian rhythms to manifest. However not only proteins display circadian oscillations. The newest research of our group shows that DNA itself manifest rhythmical behaviour.

3D chromatin architecture plays important role in control of many cellular processes like transcription, replication or repair. In vivo availability of binding sites to the regulatory factors is a key element affecting these DNA-dependent processes and spatial organisation of chromatin has a great impact on this availability. It is well documented that transcriptionally active regions tend to locate in the middle of nucleus while genes placed on the nuclear envelope are in great majority transcriptionally silent. Thus, migration of certain chromatin region from one sub-nuclear compartment to the other affects its activity and, what was recently showed, can be regulated in circadian manner. The key role in this process play two factors: CTCF and PARP1 which mediate chromatin fibres interactions and promote recruitment of circadian genes to the nuclear periphery. Induction of oscillations in the interactions between these two factors can be achieved by synchronisation of their circadian rhythm. This event is followed by oscillating recruitment of circadian loci to repressive chromatin environment at the nuclear lamina where circadian regions acquire repressive H3K9me2 mark and get transcriptionally attenuated. The process is crucial for proper functioning of living cell and its disturbance may lead to manifestation of complex diseases like cancer or diabetic. Thus, understanding of circadian migration pattern of certain chromatin regions can be a great starting point in the novel therapy of many currently untreatable genetic diseases.

About the Author

Anna Lewandowska RonnegrenAnna Lewandowska Ronnegren is a PhD student in epigenetic at Karolinska Institutet in Sweden. She tries to understand how our everyday life affects the 3D chromatin structure in the nucleus. She had been working with many different projects in a field of DNA damage, signaling pathways and circadian rhythm. Besides being an active researcher she is also a popular science freelance writer (writing for example for Wiedza i ┼╗ycie), blogger and biology advisor. Currently she is publishing her book “Laboratory techniques in molecular biology” with Medpharm publishing house. Privately the mother of two lovely boys.

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