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Pancreatic alpha and beta-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression

ABSTRACT: We performed a parallel analysis of the molecular properties of α- and β-cell oscillators, using a mouse model expressing three reporter genes: one labeling α-cells, one specific for β-cells, and a third monitoring circadian gene expression. Diurnal transcriptome analysis in separated α- and β-cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. This study represents the first parallel large-scale circadian in vivo transcriptome analysis in separated α- and β-cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE95156 | GEO | 2017/02/22

SECONDARY ACCESSION(S): PRJNA376199

REPOSITORIES: GEO

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Circadian clocks drive regeneration of pancreatic β-cells in mice

Project description:We aimed to understand the functional roles of islet cellular oscillators under diabetic conditions and during β-cell regeneration. We assessed diurnal regulation of β-cell proliferation and the transcriptional landscape in α- and residual β-cells following β-cell ablation in Insulin-rtTA/TET-DTA mice that simultaneously expressed α- and β-cell specific fluorescent reports. The mouse pancreatic islets were isolated over 24-h with 4-h interval, followed by separation of α- and β- cells using FACS sorting, RNA extraction and RNA sequencing. Acute hyperglycemia and loss of β-cell mass perturbed absolute expression levels and temporal transcriptome profiles in residual β-cells, whereas in neighboring α-cells only changes in temporal profiles were observed. Strikingly, compensatory regeneration of β-cells exhibited circadian rhythmicity. In arrhythmic Bmal1 deficient mice, massive β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia and a fatal diabetes. No compensatory proliferation of β-cells was observed in arrhythmic mice, suggesting an essential role of circadian clocks in β-cell regeneration.

2020-10-16 | GSE152751 | GEO

RNA-seq analysis in residual pancreatic β-cells of Bmal1KO/DTA mice following massive ablation

Project description:We aimed to fill the gap in understanding functional roles of the islet cellular oscillators under diabetic conditions following massive β-cell ablation, and during β-cell regeneration. We assessed diurnal regulation of β-cell proliferation and transcriptional landscape in separated α- and residual β-cells -utilizing rtTA/TET-DTA mouse model that bears α- and β-cell specific labeling. Acute hyperglycemia and loss of β-cell mass perturbed absolute expression levels and temporal transcriptome profiles in residual β-cells, whereas in neighboring α-cells only changes in temporal profiles were observed. Strikingly, compensatory regeneration of β-cells exhibited circadian rhythmicity. In arrhythmic BMAL1 knockout mice, massive β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia and a fatal non-compensated diabetes. No activation of β-cell regeneration via entry into cell-cycle was observed in arrhythmic mice, suggesting essential role of functional circadian clocks in this process.

2020-10-01 | GSE151338 | GEO

Intercellular coupling between peripheral circadian oscillators by TGF-beta signaling [RNA-seq]

Project description:Intercellular coupling is crucial to prevent desynchronization of cell-autonomous oscillator networks and thus, the disruption of circadian tissue functions. While, neuronal oscillators within the mammalian central clock, the suprachiasmatic nucleus (SCN), couple intercellularly via the exchange of secreted neurotransmitters, intercellular coupling among peripheral oscillators is highly debated and molecular mechanisms are unknown. In our study, we show that peripheral circadian oscillators couple intercellularly via the exchange of secreted signaling molecules and identify TGF-beta as peripheral coupling factor. TGF-beta signaling induces the cAMP response element dependent, immediate-early expression of the clock gene PER2, thereby phase-adjusting the molecular circadian oscillator. Genetic or pharmacologic disruption of TGF-beta signaling causes desynchronization of cellular oscillators resulting in amplitude reduction and increased sensitivity towards Zeitgeber cues. Our findings reveal a previously unknown mechanism of peripheral coupling and open a new perspective on the importance of peripheral clock synchrony for rhythmic organ functions and circadian health.

2021-07-23 | GSE158577 | GEO

Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks

Project description:Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues and induce genome-wide expression of rhythmic genes in cells. Mechanistically, RNAseq and biochemical analysis revealed the PLD2-mTORC2-AKT-GSK3β axis as a convergent pathway for both in vivo loading and hyperosmolarity-induced clock changes. These results reveal diurnal patterns of mechanical loading and consequent daily surges in osmolarity as a bona fide tissue niche-specific time cue to maintain skeletal circadian rhythms in sync.

2023-08-17 | E-MTAB-12877 | biostudies-arrayexpress

CIRP, a cold-inducible RNA-binding protein, modulates circadian gene expression posttranscriptionally

Project description:In mammalian tissues circadian gene expression can be driven by local oscillators or systemic signals controlled by the master pacemaker in the suprachiasmatic nucleus. Here we show that simulated body temperature cycles, but not peripheral oscillators, can control the rhythmic expression of Cold-Inducible RNA binding Protein (CIRP) in cultured fibroblasts. In turn, loss-of-function experiments indicate that CIRP is required for high amplitude circadian gene expression. The transcriptome-wide identification of CIRP-bound RNAs by a biotin-streptavidin based CLIP-seq procedure revealed several CIRP-bound transcripts encoding circadian oscillator proteins. One of these, CLOCK, accumulated to particularly low levels in CIRP-depleted fibroblasts. Since ectopic expression of CLOCK improved circadian gene expression in these cells, we surmise that CIRP confers robustness to circadian oscillators via the regulation of CLOCK expression. Identification of CIRP-interacting RNA molecules in NIH3T3 cells and RNA expression in NIH3T3 cells treated with Control or CIRP siRNA after incubation of the cells at 33M-BM-0C for 8 hours

2012-08-24 | E-GEOD-37685 | biostudies-arrayexpress

CIRP, a cold-inducible RNA-binding protein, modulates circadian gene expression posttranscriptionally

2012-08-24 | GSE37685 | GEO

Transcription profiling of mouse liver cells with a conditionally active liver clock to descriminate between rhythmic gene expression driven by cyclic systemic cues and local oscillators

Project description:The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) that synchronizes self-sustained oscillators in most peripheral cells. Rhythmic gene expression in peripheral tissues can be driven by cyclic systemic cues emanating from the SCN or by local oscillators. To discriminate between these two mechanisms, we engineered a mouse strain with a conditionally active liver clock. Transcriptome profiling revealed that the circadian transcription of most genes depends on functional hepatocyte clocks. However, the expression of 31 genes, including mPer2, oscillates robustly in clock-arrested hepatocytes. Such genes may be implicated in the synchronization of liver oscillators

2006-12-30 | E-MEXP-842 | biostudies-arrayexpress

Timed Exercise and Clocks: Does a Minimally Functional Suprachiasmatic Clock Support 24h Behavioral Rhythms?

Project description:The brain’s suprachiasmatic nucleus (SCN) is the master clock driving circadian rhythms in mammals. Vasoactive intestinal polypeptide (VIP) and its cognate receptor, VPAC2, are expressed in SCN neurons and mice with genetically targeted deletion of VPAC2 (Vipr2 -/-animals) show aberrant resetting to light, abnormal behavioral rhythms, and diminished SCN clock gene expression. Timed daily access to a running-wheel (scheduled voluntary exercise; SVE) promotes Vipr2 -/- SCN clock cell synchrony and 24h behavioral rhythms. We hypothesized that timed exercise alters the SCN transcriptome. Here, in control (Vipr2+/+) and Vipr2-/- mice under freely exercising and SVE conditions, RNAseq and qRT-PCR were used to measured gene expression of laser-dissected SCN. Compared to Vipr2+/+ mice, hundreds of genes were differentially expressed in the SCN from Vipr2-/- mice rhythmic in the freely exercising condition. Unexpectedly, SVE did not promote a Vipr2+/+-like SCN transcriptome in Vipr2-/- mice and many transcripts involved in SCN function including Avp, C1ql3, Gpr176, Prok2, Sst, Per2, and Nr1d1 remained dysregulated in the SVE condition. By contrast, circadian oscillators in the liver and lung were mostly intact in Vipr2-/- mice. This study indicates that marked molecular deficits in the SCN are sustained in behaviorally rhythmic Vipr2-/- mice, raising the possibility that a minimal functional SCN circadian clock can underpin whole animal rhythms.

2023-01-20 | GSE207992 | GEO

Benefit of circadian clocks in adaptive immunity and vaccination responses

Project description:The adaptive immune response is under circadian control, yet, the benefit of this rhythmicity for the organism is unknown. Furthermore, it is not understood why adaptive immune reactions continue to exhibit circadian changes over long periods of time. Using a combination of experimental and mathematical modelling approaches, we show here that dendritic cells (DCs) migrate from the skin to the draining lymph node (LN) in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Greater numbers of infiltrating DCs induce rhythmic expression of TNF-α in the draining LN, which enhances ICAM-1 expression in high endothelial venules (HEVs), resulting in lymphocyte infiltration and LN expansion. Icam1 is controlled by binding of the core circadian clock transcription factor BMAL1 to its promoter region, and rhythmic Icam1 expression is lost in mice lacking endothelial cell BMAL1. LN cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which determines the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2, as evidenced by rhythmic T cell reactions, germinal center formation and antibody production. Our results provide the mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, demonstrating its dependency upon the timing of the initial challenge and the interactions of rhythmicity in multiple parameters. This provides a strategy for using time-of-day to optimize vaccination regimes.

2023-02-08 | PXD039050 | Pride

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function

Project description:This SuperSeries is composed of the following subset Series: GSE34018: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [Expression array] GSE34019: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq] Refer to individual Series

2012-03-28 | E-GEOD-34020 | biostudies-arrayexpress

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