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      A multi-tissue multi-omics analysis reveals distinct kineztics in entrainment of diurnal transcriptomes by inverted feeding

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          Summary

          Time of eating synchronizes circadian rhythms of metabolism and physiology. Inverted feeding can uncouple peripheral circadian clocks from the central clock located in the suprachiasmatic nucleus. However, system-wide changes of circadian metabolism and physiology entrained to inverted feeding in peripheral tissues remain largely unexplored. Here, we performed a 24-h global profiling of transcripts and metabolites in mouse peripheral tissues to study the transition kinetics during inverted feeding, and revealed distinct kinetics in phase entrainment of diurnal transcriptomes by inverted feeding, which graded from fat tissue (near-completely entrained), liver, kidney, to heart. Phase kinetics of tissue clocks tracked with those of transcriptomes and were gated by light-related cues. Integrated analysis of transcripts and metabolites demonstrated that fatty acid oxidation entrained completely to inverted feeding in heart despite the slow kinetics/resistance of the heart clock to entrainment by feeding. This multi-omics resource defines circadian signatures of inverted feeding in peripheral tissues ( www.CircaMetDB.org.cn).

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          Highlights

          • A multi-omics analysis of food entrainment in mouse peripheral tissues

          • Inverted feeding rhythm entrains diurnal transcriptomes with distinct kinetics

          • Phase kinetics of tissue clocks is conditioned by constant light

          • Cardiac metabolism entrains to feeding fast with slow kinetics of the heart clock

          Abstract

          Animal Physiology ; Systems Biology ; Metabolomics ; Transcriptomics

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          Most cited references55

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          Transcriptional architecture of the mammalian circadian clock

          Next-generation sequencing approaches have yielded new insights into circadian function. Here, Takahashi reviews genome-wide analyses of the clock transcriptional feedback loop in mammals, which reveal a global circadian regulation of transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription and chromatin remodelling.
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            A circadian gene expression atlas in mammals: implications for biology and medicine.

            To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.
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              Mechanisms and regulation of cholesterol homeostasis

              Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification - a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.
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                Author and article information

                Contributors
                Journal
                iScience
                iScience
                iScience
                Elsevier
                2589-0042
                19 March 2021
                23 April 2021
                19 March 2021
                : 24
                : 4
                : 102335
                Affiliations
                [1 ]Department of Cardiology and the Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
                [2 ]Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China
                [3 ]State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
                Author notes
                []Corresponding author xyzpj@ 123456tmmu.edu.cn
                [∗∗ ]Corresponding author mindianli@ 123456tmmu.edu.cn
                [4]

                These authors contributed equally

                [5]

                Lead contact

                Article
                S2589-0042(21)00303-5 102335
                10.1016/j.isci.2021.102335
                8050734
                33889826
                1aa51c2f-e363-4270-b176-847f1605cc51
                © 2021 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 8 February 2021
                : 26 February 2021
                : 16 March 2021
                Categories
                Article

                animal physiology,systems biology,metabolomics,transcriptomics

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