bims-ciryme 2021-01-24 papers

J Biol Chem. 2020 Dec 11. pii: S0021-9258(17)50609-2. [Epub ahead of print]295(50): 17187-17199

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm.

Seref Gul, Cihan Aydin, Onur Ozcan, Berke Gurkan, Saliha Surme, Ibrahim Baris, Ibrahim Halil Kavakli.

Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box-driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1-/-Cry2-/- double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared with CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.

Keywords: CLOCK; Cryptochrome 1; allosteric regulation; allostery; circadian rhythm; clock gene; cryptochrome; gene regulation

DOI: https://doi.org/10.1074/jbc.RA120.014333

Endocrinology. 2021 Jan 16. pii: bqab009. [Epub ahead of print]

Contributions of white and brown adipose tissues to the circadian regulation of energy metabolism.

Isabel Heyde, Kimberly Begemann, Henrik Oster.

The term energy metabolism comprises the entirety of chemical processes associated with uptake, conversion, storage, and breakdown of nutrients. All these must be tightly regulated in time and space to ensure metabolic homeostasis in an environment characterized by cycles such as the succession of day and night. Most organisms evolved endogenous circadian clocks to achieve this goal. In mammals, a ubiquitous network of cellular clocks is coordinated by a pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). Adipocytes harbour their own circadian clocks and large aspects of adipose physiology are regulated in a circadian manner through transcriptional regulation of clock-controlled genes. White adipose tissue (WAT) stores energy in form of triacylglycerides at times of high energy levels which then serve as fuel in times of need. It also functions as endocrine organ releasing factors in a circadian manner to regulate food intake and energy turnover in other tissues. Brown adipose tissue (BAT) produces heat through non-shivering thermogenesis, a process also controlled by the circadian clock. We here review how WAT and BAT contribute to the circadian regulation of energy metabolism. We describe how adipose rhythms are regulated by interplay of systemic signals and local clocks and summarize how adipose-originating circadian factors feedback on metabolic homeostasis. The role of adipose tissue in circadian control of metabolism becomes increasingly clear since circadian disruption leads to alterations in adipose tissue regulation promoting obesity and its sequelae. Stabilization of adipose tissue rhythms, in turn, may help to combat disrupted energy homeostasis and obesity.

Keywords: BAT; WAT; adipose tissue; circadian clocks; energy metabolism

DOI: https://doi.org/10.1210/endocr/bqab009

Proc Natl Acad Sci U S A. 2021 Jan 26. pii: e2016878118. [Epub ahead of print]118(4):

The neuropeptide allatostatin C from clock-associated DN1p neurons generates the circadian rhythm for oogenesis.

Chen Zhang, Ivana Daubnerova, Yong-Hoon Jang, Shu Kondo, Dušan Žitňan, Young-Joon Kim.

The link between the biological clock and reproduction is evident in most metazoans. The fruit fly Drosophila melanogaster, a key model organism in the field of chronobiology because of its well-defined networks of molecular clock genes and pacemaker neurons in the brain, shows a pronounced diurnal rhythmicity in oogenesis. Still, it is unclear how the circadian clock generates this reproductive rhythm. A subset of the group of neurons designated "posterior dorsal neuron 1" (DN1p), which are among the ∼150 pacemaker neurons in the fly brain, produces the neuropeptide allatostatin C (AstC-DN1p). Here, we report that six pairs of AstC-DN1p send inhibitory inputs to the brain insulin-producing cells, which express two AstC receptors, star1 and AICR2. Consistent with the roles of insulin/insulin-like signaling in oogenesis, activation of AstC-DN1p suppresses oogenesis through the insulin-producing cells. We show evidence that AstC-DN1p activity plays a role in generating an oogenesis rhythm by regulating juvenile hormone and vitellogenesis indirectly via insulin/insulin-like signaling. AstC is orthologous to the vertebrate neuropeptide somatostatin (SST). Like AstC, SST inhibits gonadotrophin secretion indirectly through gonadotropin-releasing hormone neurons in the hypothalamus. The functional and structural conservation linking the AstC and SST systems suggest an ancient origin for the neural substrates that generate reproductive rhythms.

Keywords: Drosophila; biological clock; insulin; somatostatin; vitellogenesis

DOI: https://doi.org/10.1073/pnas.2016878118

Sci Rep. 2021 Jan 21. 11(1): 2061

Neonicotinoids disrupt memory, circadian behaviour and sleep.

Kiah Tasman, Sergio Hidalgo, Bangfu Zhu, Sean A Rands, James J L Hodge.

Globally, neonicotinoids are the most used insecticides, despite their well-documented sub-lethal effects on beneficial insects. Neonicotinoids are nicotinic acetylcholine receptor agonists. Memory, circadian rhythmicity and sleep are essential for efficient foraging and pollination and require nicotinic acetylcholine receptor signalling. The effect of field-relevant concentrations of the European Union-banned neonicotinoids: imidacloprid, clothianidin, thiamethoxam and thiacloprid were tested on Drosophila memory, circadian rhythms and sleep. Field-relevant concentrations of imidacloprid, clothianidin and thiamethoxam disrupted learning, behavioural rhythmicity and sleep whilst thiacloprid exposure only affected sleep. Exposure to imidacloprid and clothianidin prevented the day/night remodelling and accumulation of pigment dispersing factor (PDF) neuropeptide in the dorsal terminals of clock neurons. Knockdown of the neonicotinoid susceptible Dα1 and Dβ2 nicotinic acetylcholine receptor subunits in the mushroom bodies or clock neurons recapitulated the neonicotinoid like deficits in memory or sleep/circadian behaviour respectively. Disruption of learning, circadian rhythmicity and sleep are likely to have far-reaching detrimental effects on beneficial insects in the field.

DOI: https://doi.org/10.1038/s41598-021-81548-2