Clock-dependent chromatin topology modulates circadian transcription and behavior
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE101423 | GEO | 2018/03/26
REPOSITORIES: GEO
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Project description:The circadian clock dynamically rewires promoter-enhancer loops in tissues to drive robust daily rhythms in gene transcription and locomoter activity.
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Project description:The circadian clock in animals orchestrates widespread oscillatory gene expression programs, which underlie 24-h rhythms in behavior and physiology. Several studies have shown the possible roles of transcription factors and chromatin marks in controlling cyclic gene expression. However, how daily active enhancers modulate rhythmic gene transcription in mammalian tissues is not known. Using circular chromosome conformation capture (4C) combined with sequencing (4C-seq), we discovered oscillatory promoter-enhancer interactions along the 24-h cycle in the mouse liver and kidney. Rhythms in chromatin interactions were abolished in arrhythmic Bmal1 knockout mice. Deleting a contacted intronic enhancer element in the Cryptochrome 1 (Cry1) gene was sufficient to compromise the rhythmic chromatin contacts in tissues. Moreover, the deletion reduced the daily dynamics of Cry1 transcriptional burst frequency and, remarkably, shortened the circadian period of locomotor activity rhythms. Our results establish oscillating and clock-controlled promoter-enhancer looping as a regulatory layer underlying circadian transcription and behavior.
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Project description:The transcription factor Mef2 regulates activity-dependent neuronal plasticity and morphology in mammals, and clock neurons are reported to experience activity-dependent circadian remodeling in Drosophila. We show here that Mef2 is required for this daily fasciculation-defasciculation cycle. Moreover, the master circadian transcription complex CLK/CYC directly regulates Mef2 transcription. ChIP-Chip analysis identified numerous Mef2 target genes implicated in neuronal plasticity, including the cell-adhesion gene Fas2. Genetic epistasis experiments support this transcriptional regulatory hierarchy, CLK/CYC->Mef2-> Fas2, indicate that it influences the circadian fasciculation cycle within pacemaker neurons and suggest that this cycle also contributes to circadian behavior. Mef2 therefore transmits clock information to machinery involved in neuronal remodeling, which contributes to locomotor activity rhythms.
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Project description:To preserve a state of health, mammals employ an integrated network of molecular oscillators to drive daily rhythms of tissue-specific homeostatic processes. Importantly, the output, structure and coherence of this network is compromised by physiological ageing, disease and lifestyle changes. Yet, the key signalling nodes in this network, their underlying mechanisms of communication, and potential for therapeutic intervention, remain undefined. To dissect this system, we construct a minimal clock network consisting of two communicating nodes: the peripheral epidermal clock and central brain clock. We show that communication between the brain and epidermal clocks is sufficient for wiDD-type core clock activity and specific homeostatic processes, but inputs from other clock nodes are essential for full daily physiology. Unexpectedly, we find evidence that the epidermal clock selectively suppresses or interprets systemic signals to ensure coherence of specific homeostatic processes, identifying an unrecognised gatekeeper role for peripheral clocks. Together, we introduce a novel approach for dissecting a tissues daily physiology, and in turn identify key signalling nodes required to maintain epidermal homeostasis.
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Project description:The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Due to lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we present a model in which the interaction between feeding and the liver clock can be isolated in vivo by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE) in otherwise clock-less mice. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal glucose homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.
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Project description:The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Due to lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we present a model in which the interaction between feeding and the liver clock can be isolated in vivo by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE) in otherwise clock-less mice. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal glucose homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.
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Project description:Peripheral nervous system injuries lead to long-term neurological disability due to limited axonal regenerative ability. Injury-dependent and more recently injury-independent physiological mechanisms have provided important molecular insight into regenerative mechanisms. However, whether common molecular denominators underpinning both injury-dependent and independent biological processes exist remains unclear. We initially performed a comparative analysis of recently generated transcriptomic datasets associated with the regenerative ability of sciatic dorsal root ganglia (DRG). Surprisingly, circadian rhythms were identified as a the most significantly enriched biological process associated with regenerative capability. We demonstrate that DRG neurons possess an endogenous circadian clock with a 24h oscillations of circadian genes and that their regenerative ability displays a diurnal oscillation in a mouse model of sciatic nerve injury. Consistently, transcriptomic analysis of DRG neurons showed a significant time-of-day dependent enrichment for processes associated with neuronal development and axonal growth, for regeneration and circadian associated genes, including the core clock genes Bmal1 and Clock. Indeed, DRG-specific ablation of the non-redundant clock gene Bmal1showed that it is required for regenerative gene expression, neuronal intrinsic circadian axonal regeneration and target reinnervation. Lastly, Lithium, a chrono-active compound, enhanced nerve regeneration, in wildtype but not in clock genes Bmal1 and Cry1/2-deficient mice. Together, these data demonstrate that daily rhythms and the circadian clock fine-tune the regenerative response of DRG neurons, and they advocate for the use of chrono-active strategies in time-day dependent modulation of nerve repair.
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Project description:To preserve a state of health, mammals employ an integrated network of molecular oscillators to drive daily rhythms of tissue-specific homeostatic processes. Importantly, the output, structure and coherence of this network is compromised by physiological ageing, disease and lifestyle changes. Yet, the key signalling nodes in this network, their underlying mechanisms of communication, and potential for therapeutic intervention, remain undefined. To dissect this system, we construct a minimal clock network consisting of two communicating nodes: the peripheral epidermal clock and central brain clock. We show that communication between the brain and epidermal clocks is sufficient for wild-type core clock activity and specific homeostatic processes, but inputs from other clock nodes are essential for full daily physiology. Unexpectedly, we find evidence that the epidermal clock selectively suppresses or interprets systemic signals to ensure coherence of specific homeostatic processes, identifying an unrecognised gatekeeper role for peripheral clocks. Together, we introduce a novel approach for dissecting a tissues daily physiology, and in turn identify key signalling nodes required to maintain epidermal homeostasis.
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Project description:The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. The clockwork orchestrates a multitude of metabolic processes as illustrated by previous global transcriptomics and proteomics studies, and the existence of daily rhythms of reduction and oxidation (redox) in a range of diverse species. However, the reciprocal question of whether metabolism can alter the clockwork remains largely unaddressed. Here we identify the pentose phosphate pathway (PPP), a critical source of cellular reducing power in the form of NADPH, as an important modulator of circadian oscillations. We show that genetic and pharmacologic inhibition of the PPP perturbs circadian gene expression and metabolic rhythms in human cells. Pharmacologic inhibition of the PPP caused similar effects in mouse tissues, and altered the pattern of rhythmic behavior in Drosophila. These manipulations also altered genome wide DNA-binding activity of the circadian transcription factors BMAL1 and CLOCK through a mechanism likely involving the redox-sensitive histone acetyltransferase p300. Thus, disruption of the PPP regulates circadian rhythms via modulation of NADPH metabolism, highlighting redox reactions as a novel connector of metabolic cycles and transcriptional oscillations in nucleated cells.
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