Cycles in spatial and temporal chromosomal organization driven by the circadian clock

Aguilar-Arnal, Lorena; Hakim, Ofir; Patel, Vishal R.; Baldi, Pierre; Hager, Gordon L.; Sassone–Corsi, Paolo

doi:10.1038/nsmb.2667

Cited by 113 publications

(116 citation statements)

References 76 publications

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“…A recent study implicated the circadian machinery in determining temporal and spatial cycles of chromosomal organization and is capable of affecting the physical organization of the nuclear landscape via involvement of E-box elements (59). The diurnal variation of hGH1 transcript levels raises the possibility that the hGH1 locus can transit between an active and inactive chromosomal conformation in a cyclic manner daily.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Vakili¹,

Jin

Cattini

2016

Journal of Biological Chemistry

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Rhythmicity of biological functions is fundamental for optimal adaptations to environmental cues. Growth hormone (GH) is a major metabolic homeostatic factor that is secreted with a circadian pattern, but whether it is synthesized rhythmically is unknown. We used transgenic mice containing the human (h) GH gene (hGH1) locus to investigate the rhythmicity of hGH synthesis and secretion and to show that RNA and secreted protein levels oscillate over a 24-h cycle. Analysis of hGH1 promoter sequences revealed an enhancer motif (E-box) element that binds the circadian transcriptional machinery (Bmal1 and Clock). Furthermore, Bmal1/Clock were able to transactivate the hGH1 promoter, and mutation of this E-box element adversely affected basal activity after gene transfer. The ability of Bmal1 to bind the hGH1 promoter region containing the E-box element was confirmed in the hGH1 transgenic mouse pituitary in situ. Occupancy was reduced in mice fed a high fat diet during the light (inactive) stage of the daily cycle in mice and corresponded to a decrease in hGH1 RNA levels. The decreases in occupancy and RNA levels were not seen, however, during the dark (active) stage. A chromatin loop required for efficient postnatal hGH1 expression was negatively affected by the high fat diet in the light but not dark stage similar to the pattern observed with Bmal1 association with the promoter region. This is the first evidence that hGH synthesis follows a diurnal rhythm and of dynamic associations of the circadian machinery with a component of a chromosomal structure of the hGH1 locus that is essential for efficient expression.

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Section: Discussionmentioning

confidence: 99%

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Vakili¹,

Jin

Cattini

2016

Journal of Biological Chemistry

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“…This notion is relevant, because SIRT1 modulates circadian gene expression (6,9,19). Hence, intranuclear territories presenting different redox ratios could serve as a regulatory layer for circadian transcription through SIRT1 or restrict circadian transcription to subnuclear domains (41,55). An interesting case is the transcription factor CtBP that can sense free NADH, resulting in controlling its binding affinity to specific interacting proteins (40).…”

Section: Discussionmentioning

confidence: 99%

Spatial dynamics of SIRT1 and the subnuclear distribution of NADH species

Aguilar-Arnal

Ranjit

Stringari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Sirtuin 1 (SIRT1) is an NAD + -dependent deacetylase that functions as metabolic sensor of cellular energy and modulates biochemical pathways in the adaptation to changes in the environment. SIRT1 substrates include histones and proteins related to enhancement of mitochondrial function as well as antioxidant protection. Fluctuations in intracellular NAD + levels regulate SIRT1 activity, but how SIRT1 enzymatic activity impacts on NAD + levels and its intracellular distribution remains unclear. Here, we show that SIRT1 determines the nuclear organization of protein-bound NADH. Using multiphoton microscopy in live cells, we show that free and bound NADH are compartmentalized inside of the nucleus, and its subnuclear distribution depends on SIRT1. Importantly, SIRT6, a chromatin-bound deacetylase of the same class, does not influence NADH nuclear localization. In addition, using fluorescence fluctuation spectroscopy in single living cells, we reveal that NAD + metabolism in the nucleus is linked to subnuclear dynamics of active SIRT1. These results reveal a connection between NAD + metabolism, NADH distribution, and SIRT1 activity in the nucleus of live cells and pave the way to decipher links between nuclear organization and metabolism.S irtuins (SIRTs) are a conserved family of deacetylases that target a variety of proteins located in virtually all cellular compartments (1). Deacetylation by SIRTs may control many functional aspects of target proteins (2). Because SIRT deacetylase activity depends on the energy carrier NAD + , these enzymes are thought to operate as cellular metabolic sensors. In addition, because histones are targeted by nuclear SIRT, these enzymes could link variations in cellular metabolism to chromatin function.There are seven mammalian SIRTs (SIRT1 to SIRT7) with distinct subcellular locations. SIRT2 is mainly cytoplasmic; SIRT3, SIRT4, and SIRT5 are found in the mitochondrial compartment; and SIRT1, SIRT6, and SIRT7 are located in the cell nucleus (1). In mammals, SIRT1 contributes to development and protects from metabolic and cardiovascular disease, neurodegeneration, and cancer (3). SIRT1 has been reported to promote healthy aging and regulate lifespan (4, 5). At the cellular level, SIRT1 regulates lipid and glucose homeostasis, apoptosis, DNA repair, and mitochondrial function. Variations in NAD + levels control SIRT1 activity (6-9), a relevant finding in the regulation of circadian rhythms (10). Circadian rhythms in NAD + levels have been observed (11,12), which lead to fluctuating SIRT1 deacetylase activity (9) that, in turn, results into cyclic acetylation of specific SIRT1 targets (6, 9, 13). SIRT1 and SIRT6 segregate circadian metabolism by driving transcription of a differential subset of circadian genes (14). SIRT6 is a chromatinbound protein that was first characterized as a regulator of genome stability (15). The other nuclear SIRT, SIRT7, appears to be highly localized in the nucleolus and possibly involved in Pol-I-dependent transcription (16), and it has been shown to regula...

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“…The first demonstration that circadian genes are organized in functional nuclear territories was obtained by chromosome conformation capture on chip (4C) technology (71). This comprehensive study was carried out in mouse embryonic fibroblasts (MEFs) and demonstrated cyclic chromosomal arrangements using the circadian gene Dbp as bait.…”

Section: Oscillations In 3d: Revealing the Circadian Interactomementioning

confidence: 99%

“…This comprehensive study was carried out in mouse embryonic fibroblasts (MEFs) and demonstrated cyclic chromosomal arrangements using the circadian gene Dbp as bait. This gene is located in a highly gene-dense genomic environment, and its interchromosomal contacts are largely stable during the circadian cycle (71). Remarkably, a number of specific, cyclic variations in Dbp genomic interactions occur, thereby defining a circadian interactome ( Fig.…”

Section: Oscillations In 3d: Revealing the Circadian Interactomementioning

confidence: 99%

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

Aguilar-Arnal

Sassone–Corsi

2014

Proc. Natl. Acad. Sci. U.S.A.

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Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ∼24-h cycles. This control is achieved through a complex program of gene expression. In mammals, the molecular clock machinery consists of interconnected transcriptional-translational feedback loops that ultimately ensure the proper oscillation of thousands of genes in a tissue-specific manner. To achieve circadian transcriptional control, chromatin remodelers serve the clock machinery by providing appropriate oscillations to the epigenome. Recent findings have revealed the presence of circadian interactomes, nuclear "hubs" of genome topology where coordinately expressed circadian genes physically interact in a spatial and temporal-specific manner. Thus, a circadian nuclear landscape seems to exist, whose interplay with metabolic pathways and clock regulators translates into specific transcriptional programs. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control.circadian rhythms | chromatin | epigenetics | nuclear organization

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Cycles in spatial and temporal chromosomal organization driven by the circadian clock

Cited by 113 publications

References 76 publications

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Spatial dynamics of SIRT1 and the subnuclear distribution of NADH species

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

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