Circadian control of the secretory pathway is a central mechanism in tissue homeostasis

Chang, Joan; Garva, Richa; Pickard, Adam; Yeung, Ching-Yan Chloé; Mallikarjun, Venkatesh; Swift, Joe; Holmes, David; Calverley, Ben; Lu, Yinhui; Adamson, Antony; Raymond-Hayling, Helena; Jensen, Oliver E.; Shearer, Tom; Meng, Qing‐Jun; Kadler, Karl E.

doi:10.1101/304014

Cited by 4 publications

(6 citation statements)

References 81 publications

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“…Dysregulation of these genes in Bmal1 KO cartilage suggests endogenous clock control in contrast to merely responding to daily mechanical loading. This is in line with recent study by Chang et al [26] showing that collagen type I in mouse tail tendon is rhythmically secreted and assembled and that ~10% of tendon proteome is rhythmic. Consistent with these findings, a large portion of the machinery related to protein synthesis exhibited a circadian pattern in abundance in cartilage.…”

Section: Discussionsupporting

confidence: 92%

Circadian time series proteomics reveals daily dynamics in cartilage physiology

Dudek

Angelucci

Ruckshanthi

et al. 2019

Preprint

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Objectives: Articular cartilage undergoes cyclical heavy loading and low load recovery during the 24-hour day/night cycle. We investigated the daily changes of protein abundance in mouse femoral head articular cartilage by performing 24-hour timeseries proteomics study.Methods: Tandem mass spectrometry analysis was used to quantify proteins extracted from mouse cartilage. Bioinformatics analysis was performed to quantify rhythmic changes in protein abundance. Primary chondrocytes were isolated and cultured for independent validation of selected rhythmic proteins.Results: 145 rhythmic proteins were detected. Among these were key cartilage molecules including CCN2, MATN1, PAI-1 and PLOD1 & 2. Pathway analysis revealed that proteins related to protein synthesis, cytoskeleton and glucose metabolism exhibited time-of-day dependent peaks in their abundance. Meta-analysis of published proteomics datasets from articular cartilage revealed that numerous rhythmic proteins were dysregulated in osteoarthritis and/or ageing. Conclusions:Our circadian proteomics study revealed that articular cartilage is a much more dynamic tissue than previously thought. Chondrocytes exhibit circadian rhythms not only in gene expression but also in protein abundance. Our results clearly call for the consideration of circadian timing in understanding cartilage biology, osteoarthritis pathogenesis, treatment strategies and biomarker detection.

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Section: Discussionsupporting

confidence: 92%

Circadian time series proteomics reveals daily dynamics in cartilage physiology

Dudek

Angelucci

Ruckshanthi

et al. 2019

Preprint

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“…Due to the small dispersion angles of the fibrils, this effect should be minimal, however, for future analysis, especially when tortuosity is high, methods such as elliptical fitting could provide a more accurate measurement of fibril diameter [14]. Fibril distribution has recently been related to circadian control [49]; however, our study did not control time of day or address this potential mechanism.…”

Section: Discussionmentioning

confidence: 94%

Helical fibrillar microstructure of tendon using serial block-face scanning electron microscopy and a mechanical model for interfibrillar load transfer

Safa

Peloquin

Natriello

et al. 2019

J. R. Soc. Interface.

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Tendon's hierarchical structure allows for load transfer between its fibrillar elements at multiple length scales. Tendon microstructure is particularly important, because it includes the cells and their surrounding collagen fibrils, where mechanical interactions can have potentially important physiological and pathological contributions. However, the three-dimensional (3D) microstructure and the mechanisms of load transfer in that length scale are not known. It has been postulated that interfibrillar matrix shear or direct load transfer via the fusion/branching of small fibrils are responsible for load transfer, but the significance of these mechanisms is still unclear. Alternatively, the helical fibrils that occur at the microstructural scale in tendon may also mediate load transfer; however, these structures are not well studied due to the lack of a three-dimensional visualization of tendon microstructure. In this study, we used serial block-face scanning electron microscopy to investigate the 3D microstructure of fibrils in rat tail tendon. We found that tendon fibrils have a complex architecture with many helically wrapped fibrils. We studied the mechanical implications of these helical structures using finite-element modelling and found that frictional contact between helical fibrils can induce load transfer even in the absence of matrix bonding or fibril fusion/branching. This study is significant in that it provides a three-dimensional view of the tendon microstructure and suggests friction between helically wrapped fibrils as a mechanism for load transfer, which is an important aspect of tendon biomechanics.

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“…In addition, Golgi vesicle transport was found to be enriched for both the set of candidate genes with 24-h and with 12-h rhythmic phase-shifted isoforms, suggesting a complex temporal regulation of the secretory pathway that may possibly be regulated via circadian and ultradian splice isoform production. AS events have recently been shown to affect the secretory pathway [53] and a circadian control of procollagen transport from ER-to-Golgi and Golgi-to-plasma membrane has been reported in mice [54]. Among the genes with 24-h rhythmic phase-shifted isoform pairs in multiple baboon tissues, we identified several oncogenes and cancer-related genes, including PCBP2 , NELFE , CIRBP , and RACK1 .…”

Section: Discussionmentioning

confidence: 97%

A Computational Analysis of Alternative Splicing across Mammalian Tissues Reveals Circadian and Ultradian Rhythms in Splicing Events

El-Athman

Knezevic

Fuhr

et al. 2019

IJMS

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Mounting evidence points to a role of the circadian clock in the temporal regulation of post-transcriptional processes in mammals, including alternative splicing (AS). In this study, we carried out a computational analysis of circadian and ultradian rhythms on the transcriptome level to characterise the landscape of rhythmic AS events in published datasets covering 76 tissues from mouse and olive baboon. Splicing-related genes with 24-h rhythmic expression patterns showed a bimodal distribution of peak phases across tissues and species, indicating that they might be controlled by the circadian clock. On the output level, we identified putative oscillating AS events in murine microarray data and pairs of differentially rhythmic splice isoforms of the same gene in baboon RNA-seq data that peaked at opposing times of the day and included oncogenes and tumour suppressors. We further explored these findings using a new circadian RNA-seq dataset of human colorectal cancer cell lines. Rhythmic isoform expression patterns differed between the primary tumour and the metastatic cell line and were associated with cancer-related biological processes, indicating a functional role of rhythmic AS that might be implicated in tumour progression. Our data shows that rhythmic AS events are widespread across mammalian tissues and might contribute to a temporal diversification of the proteome.

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Circadian control of the secretory pathway is a central mechanism in tissue homeostasis

Cited by 4 publications

References 81 publications

Circadian time series proteomics reveals daily dynamics in cartilage physiology

Circadian time series proteomics reveals daily dynamics in cartilage physiology

Helical fibrillar microstructure of tendon using serial block-face scanning electron microscopy and a mechanical model for interfibrillar load transfer

A Computational Analysis of Alternative Splicing across Mammalian Tissues Reveals Circadian and Ultradian Rhythms in Splicing Events

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