Effects of Diurnal Variation of Gut Microbes and High-Fat Feeding on Host Circadian Clock Function and Metabolism

Cell Host & Microbe, Год журнала: 2015, Номер 17(5), С. 681 - 689

Опубликована: Апрель 17, 2015

Язык: Английский

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Pancreatic β cell enhancers regulate rhythmic transcription of genes controlling insulin secretion

Science, Год журнала: 2015, Номер 350(6261)

Опубликована: Ноя. 5, 2015

The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior metabolism with solar cycle. Genetic or environmental perturbation circadian cycles contributes to metabolic disorders including type 2 diabetes. To study impact cell-autonomous on pancreatic β cell function, we examined islets from mice either intact disrupted expression both throughout life limited adulthood. We found pronounced oscillation insulin secretion was synchronized genes encoding secretory machinery signaling regulate release. CLOCK/BMAL1 colocalized factor PDX1 within active enhancers distinct those controlling rhythmic gene networks in liver. also ablation adult caused severe glucose intolerance. Thus, type-specific underlie control peripheral may help explain its dysregulation

Язык: Английский

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Guidelines for Genome-Scale Analysis of Biological Rhythms

Journal of Biological Rhythms, Год журнала: 2017, Номер 32(5), С. 380 - 393

Опубликована: Окт. 1, 2017

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout day. These methods hold significant promise for future discovery, when combined with computational modeling. However, genome-scale experiments are costly laborious, yielding “big data” that conceptually statistically difficult analyze. There is no obvious consensus regarding design or analysis. Here we discuss relevant technical considerations generate reproducible, sound, broadly useful data. Rather than suggest a set rigid rules, aim codify principles by which investigators, reviewers, readers primary literature can evaluate suitability different experimental designs measuring aspects rhythms. We introduce CircaInSilico, web-based application generating synthetic genome data benchmark statistical studying Finally, several unmet analytical needs, applications clinical medicine, productive avenues address them.

Язык: Английский

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A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

Cell, Год журнала: 2015, Номер 162(4), С. 836 - 848

Опубликована: Авг. 1, 2015

Язык: Английский

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Circadian rhythms in the absence of the clock gene Bmal1

Science, Год журнала: 2020, Номер 367(6479), С. 800 - 806

Опубликована: Фев. 14, 2020

Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is principal driver of molecular clock mammals. Bmal1 deletion abolishes 24-hour activity patterning, one measure output. We determined whether function necessary for oscillations skin fibroblasts and liver slices. Unexpectedly, knockout mice, both tissues exhibited the transcriptome, proteome, phosphoproteome over 2 to 3 days absence any exogenous drivers such as light or temperature cycles. This demonstrates competent pacemaker knockouts. suggest that might be underpinned by transcriptional regulation recruitment ETS family factors, nontranscriptionally co-opting redox oscillations.

Язык: Английский

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NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging

Molecular Cell, Год журнала: 2020, Номер 78(5), С. 835 - 849.e7

Опубликована: Май 4, 2020

Язык: Английский

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A photoregulatory mechanism of the circadian clock in Arabidopsis

Nature Plants, Год журнала: 2021, Номер 7(10), С. 1397 - 1408

Опубликована: Окт. 14, 2021

Язык: Английский

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Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity

Cell Metabolism, Год журнала: 2024, Номер 36(1), С. 90 - 102.e7

Опубликована: Янв. 1, 2024

Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity function within multicellular tissues through incompletely known mechanisms. By assembling a atlas of chromatin state human islets, we identified β cell subtypes governed by either high or low activity the factor pancreatic duodenal homeobox-1 (PDX1). cells with reduced PDX1 displayed increased accessibility at latent nuclear κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression NF-κB impaired glucose tolerance night. Three-dimensional analyses in tandem immunoprecipitation (ChIP) sequencing revealed that silences circadian inflammatory enhancers long-range contacts involving SIN3A. Conversely, Bmal1 ablation disrupted genome-wide DNA binding. Finally, antagonizing interleukin (IL)-1β receptor, an target, improved insulin secretion islets. Our studies reveal functional single defined gradient identify as target for insulinotropic therapy.

Язык: Английский

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Universal method for robust detection of circadian state from gene expression

Proceedings of the National Academy of Sciences, Год журнала: 2018, Номер 115(39)

Опубликована: Сен. 10, 2018

Circadian clocks play a key role in regulating vast array of biological processes, with significant implications for human health. Accurate assessment physiological time using transcriptional biomarkers found blood can significantly improve diagnosis circadian disorders and optimize the delivery therapeutic treatments. To be useful, such test must accurate, minimally burdensome to patient, readily generalizable new data. A major obstacle development gene expression biomarker tests is diversity measurement platforms inherent variability data, often resulting predictors that perform well original datasets but cannot universally applied samples collected other settings. Here, we introduce TimeSignature, an algorithm robustly infers from expression. We demonstrate its application data three independent studies distinct microarrays further validate it against set profiled by RNA-sequencing. Our results show TimeSignature more accurate efficient than competing methods, estimating within 2 h majority samples. Importantly, once trained on single study, predictor yield highly differences study population, patient protocol, or assay platform without renormalizing retraining. This feature unique among expression-based addresses challenge generalizable, clinically useful tests.

Язык: Английский

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Circadian deep sequencing reveals stress-response genes that adopt robust rhythmic expression during aging

Nature Communications, Год журнала: 2017, Номер 8(1)

Опубликована: Фев. 21, 2017

Abstract Disruption of the circadian clock, which directs rhythmic expression numerous output genes, accelerates aging. To enquire how system protects aging organisms, here we compare transcriptomes in heads young and old Drosophila melanogaster . The core clock most genes remained robustly flies, while others lost rhythmicity with age, resulting constitutive over- or under-expression. Unexpectedly, identify a subset that adopted increased de novo during aging, enriched for stress-response functions. These termed late-life cyclers, were also rhythmically induced flies by constant exposure to exogenous oxidative stress, this upregulation is CLOCK-dependent. We age-onset several putative primary piRNA transcripts overlapping antisense transposons. Our results suggest that, as organisms shifts greater regulatory priority mitigation accumulating cellular stress.

Язык: Английский

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