Genome Biol, auth.: group Gatfield

Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms

Hima Priyanka Nadimpalli # 1Georgia Katsioudi # 1Enes Salih Arpa # 1Lies Chikhaoui 1Alaaddin Bulak Arpat 1Angelica Liechti 1Gaël Palais 2Claudia Tessmer 3Ilse Hofmann 3Bruno Galy 2David Gatfield 4

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Background: Cellular iron homeostasis is regulated by iron regulatory proteins (IRP1 and IRP2) that sense iron levels (and other metabolic cues) and modulate mRNA translation or stability via interaction with iron regulatory elements (IREs). IRP2 is viewed as the primary regulator in the liver, yet our previous datasets showing diurnal rhythms for certain IRE-containing mRNAs suggest a nuanced temporal control mechanism. The purpose of this study is to gain insights into the daily regulatory dynamics across IRE-bearing mRNAs, specific IRP involvement, and underlying systemic and cellular rhythmicity cues in mouse liver.

Results: We uncover high-amplitude diurnal oscillations in the regulation of key IRE-containing transcripts in the liver, compatible with maximal IRP activity at the onset of the dark phase. Although IRP2 protein levels also exhibit some diurnal variations and peak at the light-dark transition, ribosome profiling in IRP2-deficient mice reveals that maximal repression of target mRNAs at this timepoint still occurs. We further find that diurnal regulation of IRE-containing mRNAs can continue in the absence of a functional circadian clock as long as feeding is rhythmic.

Conclusions: Our findings suggest temporally controlled redundancy in IRP activities, with IRP2 mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. Moreover, we highlight the significance of feeding-associated signals in driving rhythmicity. Our work highlights the dynamic nature and regulatory complexity in a metabolic pathway that had previously been considered well-understood.

Mol Cell, auth.: group Roignant

DDX21: The link between m6A and R-loops comment

Guillaume Lavergne 1Jean-Yves Roignant 2

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In this issue of Molecular Cell, Hao et al.1 demonstrate that the RNA helicase DDX21 recruits the m6A methyltransferase complex to R-loops, ensuring proper transcription termination and genome stability.

Commun Biol, co-auth.: group Benton

Chemogenetic activation of mammalian brain neurons expressing insect Ionotropic Receptors by systemic ligand precursor administration

Yoshio Iguchi 1Ryoji Fukabori 1Shigeki Kato 1Kazumi Takahashi 2Satoshi Eifuku 2Yuko Maejima 3Kenju Shimomura 3Hiroshi Mizuma 4 5Aya Mawatari 6Hisashi Doi 6 7Yilong Cui 8Hirotaka Onoe 9Keigo Hikishima 10Makoto Osanai 11Takuma Nishijo 12 13Toshihiko Momiyama 12Richard Benton 14Kazuto Kobayashi 15

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Chemogenetic approaches employing ligand-gated ion channels are advantageous regarding manipulation of target neuronal population functions independently of endogenous second messenger pathways. Among them, Ionotropic Receptor (IR)-mediated neuronal activation (IRNA) allows stimulation of mammalian neurons that heterologously express members of the insect chemosensory IR repertoire in response to their cognate ligands. In the original protocol, phenylacetic acid, a ligand of the IR84a/IR8a complex, was locally injected into a brain region due to its low permeability of the blood-brain barrier. To circumvent this invasive injection, we sought to develop a strategy of peripheral administration with a precursor of phenylacetic acid, phenylacetic acid methyl ester, which is efficiently transferred into the brain and converted to the mature ligand by endogenous esterase activities. This strategy was validated by electrophysiological, biochemical, brain-imaging, and behavioral analyses, demonstrating high utility of systemic IRNA technology in the remote activation of target neurons in the brain.

Physiol Rev. Auth. B.Thorens

Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion Review

Bernard Thorens 1

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Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle or glucose production by the liver. The balance between the secretion of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet b-cells and a-cells can sense variations in glycemia and respond by an appropriate secretory response to restore euglycemia. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and, thus, a vital interest in ensuring that glycemic levels never fall below ~5mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cells secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we will present the autonomic innervation of the pancreatic islets; the mechanisms of neurons activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow to integrate specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function. Finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.

Int J Mol Sci. auth.: W.Wahli

PPARs as Key Transcription Regulators at the Crossroads of Metabolism and Inflammation Editorial

Manuel Vázquez-Carrera 1 2 3 4Walter Wahli 5 6 7

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The metabolic and immune systems are complex networks of organs, cells, and proteins that are involved in the extraction of energy from food; this is to run complex cellular processes and defend the body against infections while protecting its own tissues, respectively […].

ERC Advanced Grant 2024

The ERC Advanced Grant 2024 (ERC-2024-ADG) call opened 29 May 2024 with a submission deadline on 29 Aug 2024. Swiss-based researchers are eligible to apply.  

Researchers of all career stages who have a track-record of significant research achievements and are leaders in their field may apply for this 5-year grant (budget up to EUR 2.5 M). 

>> Link to the call

Information and advice (buget, Institutional Support Letter, etc.) :