Noyau suprachiasmatique | EPFL Graph Search

Le noyau suprachiasmatique (NSC) est une structure médiane bilatérale du cerveau d'environ comprenant environ et située dans l'hypothalamus, juste au-dessus du chiasma optique. Il est responsable du contrôle des rythmes circadiens. Les activités neuronales et hormonales qu'il génère régulent différentes fonctions dans un cycle circadien (de ). Le NSC interagit avec de nombreuses régions dans le cerveau. Il contient différents types cellulaires et sécrète différents peptides (comme la vasopressine et le peptide vasoactif intestinal), ainsi que différents neurotransmetteurs. Le noyau suprachiasmatique est situé dans la partie antérieure de l'hypothalamus, juste au-dessus du chiasma optique et des deux côtés du troisième ventricule. Le noyau suprachiasmatique est commandé par une petite voie nerveuse, la projection rétinohypothalamique (RH), qui relie ce noyau au tractus optique, situé juste en dessous de lui. De nombreux aspects du comportement des mammifères comportent un rythme circadien (le sommeil, l'activité physique, la vigilance, les taux d'hormones, la température du corps, les fonctions immunitaires et la digestion). Le NSC contrôle les rythmes circadiens. Dans le cas du sommeil, par exemple, la durée totale est maintenue chez les rats avec une lésion du NSC mais la durée et l'organisation des phases de sommeil deviennent imprévisibles. En effet, ce rythme circadien est perdu lors de l'ablation du NSC. Le NSC contrôle des « oscillateurs esclaves » dans les tissus périphériques, qui montrent leur propre rythmicité de 24 heures mais qui se synchronisent avec le NSC. Le NSC reçoit des informations depuis des cellules ganglionnaires photosensibles sur la rétine, via le tractus rétinohypothalamique. Les neurones dans le NSC ventrolatéral ont la capacité d'avoir une expression génique induite par la lumière. Les cellules ganglionnaires contenant de la mélanopsine dans la rétine ont une connexion directe au NSC ventrolatéral (NSCvl) par le tractus rétinohypothalamique.

Rhythmic and clock-dependent chromatin loops regulate circadian gene expression

Jérôme Mermet

In mammals the circadian clock drives daily behavioural and physiological changes that resonate with environmental cues, which can be observed, for example, in the intricate timing of rest during the night and activity during the day in humans. The circadian clock consists of a network of hierarchical clocks in which the central pacemaker is located in the suprachiasmatic nucleus, which is sensitive to external light and propagates time to the peripheral organ-based clocks. Within organs, clocks tick in each individual cell and are molecularly encoded in the genome as a network of dynamic feedback loops. By mediating the expression of the appropriate gene products at the correct moment of the day, the molecular clocks op-timize physiological functions of virtually every cell in our body, allowing us to synchronize with daily fluc-tuations in the environment. In mammalian cells the chromatin organization in the nucleus consists of a topological network, in which chromatin interactions between distal regulatory elements such as enhancers and target genes are essen-tial to regulate gene expression. Important questions remain: is the complex chromatin folding dynamic and if so on which genomic and temporal scales? In fact, dynamic rearrangements of the chromatin have been reported on multiple genomic and time scales, from the entire genome to enhancer-promoter con-tacts, across developmental transitions, cellular differentiation, and transcription cycles. With this per-spective in mind, the circadian oscillator provides a unique model to study the dynamics of genomic inter-actions in the context of fluctuating transcription. Here, we explored chromatin contacts of core-clock and clock-controlled gene promoters in the mouse. We aimed at evaluating the putative dynamics of chromatin contacts, at estimating their conservation across tissues, and at exploring the contribution of the circadian clock to this interaction network. To achieve this goal, we performed 4C-sequencing assays at two circadian time points in the liver and kidney of WT and clock-deficient animals. Overall, we observe that chromatin contacts are largely conserved across circadian time points and genetic backgrounds, and are tissue-specific. Our experiments reveal that the promoters of core-clock and clock-controlled genes contact distal genomic regions containing en-hancer chromatin signatures, suggesting a functional role of these distal sites in target gene regulation. Our data also suggest a clock-driven module of rhythmic genes that are colocalized in the nucleus. However, we also observe dynamic contacts between oscillating gene promoter and enhancer-like ge-nomic regions. In this thesis, we discuss in detail two examples of dynamic chromatin looping that are ob-served at the Cry1 and Gys2 loci. Our data reveal not only a dynamic coupling between the chromatin loop and the transcriptional state but also that the dynamic of chromatin looping depends on a functional clock. Furthermore, genome editing experiments using CRISPR-Cas9 tools reveal that the Cry1 distal site is essential for the transcriptional regulation of Cry1 and contributes to the circadian clock robustness both in-vivo and in cultured cells. These results demonstrate how local chromatin rearrangements take place in a 24-hour time-scale and set chromatin looping between gene promoters and distal regions as a new reg-ulatory layer for circadian gene expression.

EPFL2017

Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World

Felix Naef, Jake Yeung, Jérôme Mermet

Mammals have evolved an internal timing system, the circadian clock, which synchronizes physiology and behavior to the daily light and dark cycles of the Earth. The master clock, located in the suprachiasmatic nucleus (SCN) of the brain, takes fluctuating light input from the retina and synchronizes other tissues to the same internal rhythm. The molecular clocks that drive these circadian rhythms are ticking in nearly all cells in the body. Efforts in systems chronobiology are now being directed at understanding, on a comprehensive scale, how the circadian clock controls different layers of gene regulation to provide robust timing cues at the cellular and tissue level. In this review, we introduce some basic concepts underlying periodicity of gene regulation, and then highlight recent genome-wide investigations on the propagation of rhythms across multiple regulatory layers in mammals, all the way from chromatin conformation to protein accumulation.

Cold Spring Harbor Lab Press, Publications Dept2017

Rhythmic and clock-dependent chromatin loops regulate circadian gene expression

Jérôme Mermet

EPFL2017