Adaptation of molecular circadian clockwork to environmental changes: a role for alternative splicing and miRNAs

Bartok, Osnat; Kyriacou, Charalambos P.; Levine, Joel D.; Sehgal, Amita; Kadener, Sebastián

doi:10.1098/rspb.2013.0011

Cited by 31 publications

(32 citation statements)

References 62 publications

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“…In addition, miRNA concentrations could be influenced by sample hemolysis and processing such as chloroform extraction (38) and may be prone to diurnal and seasonal variations. (99) To minimize those sources of variation we applied strictest quality controls and also checked for hemolysis. (38) In addition, we made sure that the blood draw was carried out in a fasting state and during a standardized time-window of the day (between 8:00 a.m. and 11:00 a.m.).…”

Section: Discussionmentioning

confidence: 99%

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

Heilmeier

Hackl²,

Skalicky

et al. 2016

Journal of Bone and Mineral Research

122

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Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well-characterized study of diabetic bone disease and postmenopausal osteoporosis (n ¼ 80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA-qPCR-arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes-related fractures with high specificity and sensitivity (area under the receiver-operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture-indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue-derived mesenchymal stem cells to investigate the effect of miR-550a-5p, miR-188-3p, and miR-382-3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR-382-3p significantly enhanced osteogenic differentiation (p < 0.001), whereas miR-550a-5p inhibited this process (p < 0.001). Both miRNAs, miR-382-3p and miR-550a-5p, impaired adipogenic differentiation, whereas miR-188-3p did not exert an effect on adipogenesis. None of the miRNAs affected significantly cell proliferation. Our data suggest for the first time that miRNAs are linked to fragility fractures in T2D postmenopausal women and should be further investigated for their diagnostic potential and their detailed function in diabetic bone.

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Section: Discussionmentioning

confidence: 99%

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

Heilmeier

Hackl²,

Skalicky

et al. 2016

Journal of Bone and Mineral Research

122

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“…24-hour period that enables organisms to synchronize biological processes with the day-night-cycle [23]. In plants, the circadian clock coordinates a plethora of physiological processes, including rhythmic leaf movements, stomata aperture and flower opening [24,25].…”

Section: Temperature Regulated As Modulates the Circadian Clockmentioning

confidence: 99%

Role of alternative pre-mRNA splicing in temperature signaling

Capovilla

Pajoro

Immink

et al. 2015

Current Opinion in Plant Biology

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“…D. melanogaster is an excellent model system to study mechanisms governing circadian rhythms and sleep [8–10], and in addition undergoes thermal adjustments in its daily behavior [4, 11–15]. Like many animals, Drosophila melanogaster exhibits a bimodal activity pattern with major bouts in the morning and evening that are separated by a mid-day siesta, whereas the majority of sleep occurs at night [16].…”

Section: Introductionmentioning

confidence: 99%

Mid-day siesta in natural populations of D. melanogaster from Africa exhibits an altitudinal cline and is regulated by splicing of a thermosensitive intron in the period clock gene

Cao

Edery

2017

BMC Evol Biol

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BackgroundMany diurnal animals exhibit a mid-day ‘siesta’, generally thought to be an adaptive response aimed at minimizing exposure to heat on warm days, suggesting that in regions with cooler climates mid-day siestas might be a less prominent feature of animal behavior. Drosophila melanogaster exhibits thermal plasticity in its mid-day siesta that is partly governed by the thermosensitive splicing of the 3’-terminal intron (termed dmpi8) from the key circadian clock gene period (per). For example, decreases in temperature lead to progressively more efficient splicing, which increasingly favors activity over sleep during the mid-day. In this study we sought to determine if the adaptation of D. melanogaster from its ancestral range in the lowlands of tropical Africa to the cooler temperatures found at high altitudes involved changes in mid-day sleep behavior and/or dmpi8 splicing efficiency.ResultsUsing natural populations of Drosophila melanogaster from different altitudes in tropical Africa we show that flies from high elevations have a reduced mid-day siesta and less consolidated sleep. We identified a single nucleotide polymorphism (SNP) in the per 3’ untranslated region that has strong effects on dmpi8 splicing and mid-day sleep levels in both low and high altitude flies. Intriguingly, high altitude flies with a particular variant of this SNP exhibit increased dmpi8 splicing efficiency compared to their low altitude counterparts, consistent with reduced mid-day siesta. Thus, a boost in dmpi8 splicing efficiency appears to have played a prominent but not universal role in how African flies adapted to the cooler temperatures at high altitude.ConclusionsOur findings point towards mid-day sleep behavior as a key evolutionary target in the thermal adaptation of animals, and provide a genetic framework for investigating daytime sleep in diurnal animals which appears to be driven by mechanisms distinct from those underlying nighttime sleep.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-017-0880-8) contains supplementary material, which is available to authorized users.

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Adaptation of molecular circadian clockwork to environmental changes: a role for alternative splicing and miRNAs

Cited by 31 publications

References 62 publications

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

Role of alternative pre-mRNA splicing in temperature signaling

Mid-day siesta in natural populations of D. melanogaster from Africa exhibits an altitudinal cline and is regulated by splicing of a thermosensitive intron in the period clock gene

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