microRNA Modulation of Circadian-Clock Period and Entrainment

Department of Neuroscience, Ohio State University, Columbus, OH 43210, USA.
Neuron (Impact Factor: 15.05). 07/2007; 54(5):813-29. DOI: 10.1016/j.neuron.2007.05.017
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microRNAs (miRNAs) are a class of small, noncoding RNAs that regulate the stability or translation of mRNA transcripts. Although recent work has implicated miRNAs in development and in disease, the expression and function of miRNAs in the adult mammalian nervous system have not been extensively characterized. Here, we examine the role of two brain-specific miRNAs, miR-219 and miR-132, in modulating the circadian clock located in the suprachiasmatic nucleus. miR-219 is a target of the CLOCK and BMAL1 complex, exhibits robust circadian rhythms of expression, and the in vivo knockdown of miR-219 lengthens the circadian period. miR-132 is induced by photic entrainment cues via a MAPK/CREB-dependent mechanism, modulates clock-gene expression, and attenuates the entraining effects of light. Collectively, these data reveal miRNAs as clock- and light-regulated genes and provide a mechanistic examination of their roles as effectors of pacemaker activity and entrainment.

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    • "4374966, Life Technologies ) were used for microRNA and mRNA, respectively, according to the manufacturer's recommended protocols. For microRNA analysis, we selected eight specific microRNA assays based on evidence for their expression in the hypothalamus (let-7a, let-7b, mir-124a, mir-132, mir-145, mir-219, mir-7, mir-9) (Sakai et al., 2013; Davis et al., 2012; Cheng et al., 2007). Due to the small amount of starting material, only biological replicates were used for analysis. "
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    ABSTRACT: This study examined developmental changes and sexual dimorphisms in hypothalamic microRNAs, and whether gestational exposures to environmental endocrine-disrupting chemicals (EDCs) altered their expression patterns. Pregnant rat dams were treated on gestational days 16 and 18 with vehicle, estradiol benzoate, or a mixture of polychlorinated biphenyls. Male and female offspring were euthanized on postnatal days (P) 15, 30, 45, or 90, and microRNA and mRNA targets were quantified in the medial preoptic nucleus (MPN) and ventromedial nucleus (VMN) of the hypothalamus. MicroRNAs showed robust developmental changes in both regions, and were sexually dimorphic in the MPN, but not VMN. Importantly, microRNAs in females were up-regulated by EDCs at P30, and down-regulated in males at P90. Few changes in mRNAs were found. Thus, hypothalamic microRNAs are sensitive to prenatal EDC treatment in a sex-, developmental age-, and brain region-specific manner. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 07/2015; 414. DOI:10.1016/j.mce.2015.07.013 · 4.41 Impact Factor
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    • "Our findings of an association between PER3-VNTR and TOL should be replicated in an independent sample in a future study, which should control for history of shift work and transmeridian travel, as well as sleep timing and intake of caffeinated beverages during several hours prior to the testing. A future analysis of polymorphisms and epigenetic variants in other genes related to circadian rhythms and neural and synaptic plasticity could be helpful to understand in further detail the molecular correlates of planning abilities (Bhatti et al., 2014; Cheng et al., 2007; Strazisar et al., 2014), which could contribute to a more complete knowledge about normal cognitive functions and related neuropsychiatric disorders (Alaerts et al., 2009; Forero et al., 2009). "
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    ABSTRACT: Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive-compulsive disorder and Parkinson's disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian clock gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3-VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogotá, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p = 0.003). These results appear to be independent from effects of this polymorphism on self-reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders.
    Chronobiology International 03/2015; 32(5):591-595. DOI:10.3109/07420528.2015.1014096 · 3.34 Impact Factor
    • "MicroRNAs are of great interest for various forensic applications [5], due to their small size, tissue specific expression and higher resistance to degradation compared to mRNA, and were previously proposed as suitable markers for forensic body fluid identification [10] [11] [12]. In recent years various microRNAs have been implied in the regulation of circadian clock [13] [14] [15], and some of them were shown to exhibit diurnal expression changes in diverse tissues, such as liver or suprachiasmatic nucleus (SCN) [14] [15]. "
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    ABSTRACT: A recent proof-of-concept pilot study proposed using microRNA (miRNA) markers for time of death determination. The markers - miRNA-142-5p and miRNA-541, were reported to show considerable expression differences in vitreous humor between individuals who died during the day or night. Here, we investigated whether these miRNA markers show the same diurnal expression pattern in blood, which would make them useful for estimating bloodstain deposition time to allow molecular alibi testing for forensic casework. We analyzed venous blood samples collected from 12 healthy individuals every 4h during the 24hday/night period under controlled sleep-laboratory conditions. MiRNA-142-5p normalized against miRNA-222 showed no statistically significant expression differences between blood samples collected during daytime and nighttime (one-way ANOVA p=0.81), and also no statistically significant rhythmicity during the 24hday/night period (cosine fit for all individuals p>0.05, averaged data p=0.932). MicroRNA-541 amplification in blood was above the 34-cycle threshold applied in the study, indicating too low quantities for obtaining reliable data. Overall, we conclude that the two miRNA markers previously suggested for time of death determination in vitreous humor are not suitable for estimating the deposition time of forensic bloodstains. Future studies may find out if miRNA markers with significant diurnal expression patterns can be identified and how useful they would be for forensic trace deposition timing.
    Forensic Science International: Genetics 06/2014; 12C:181-184. DOI:10.1016/j.fsigen.2014.06.008 · 4.60 Impact Factor
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