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 […].

Biochim Biophys Acta Mol Cell Res, auth.: group Fajas

E2F transcription factor-1 modulates expression of glutamine metabolic genes in mouse embryonic fibroblasts and uterine sarcoma cells

Katharina Huber 1Albert Giralt 2René Dreos 2Helene Michenthaler 3Sarah Geller 2Valentin Barquissau 2Dorian V Ziegler 2Daniele Tavernari 4Hector Gallart-Ayala 5Katarina Krajina 6Katharina Jonas 6Giovanni Ciriello 4Julijana Ivanisevic 5Andreas Prokesch 7Martin Pichler 8Lluis Fajas 9

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Free article


Metabolic reprogramming is considered as a hallmark of cancer and is clinically exploited as a novel target for therapy. The E2F transcription factor-1 (E2F1) regulates various cellular processes, including proliferative and metabolic pathways, and acts, depending on the cellular and molecular context, as an oncogene or tumor suppressor. The latter is evident by the observation that E2f1-knockout mice develop spontaneous tumors, including uterine sarcomas. This dual role warrants a detailed investigation of how E2F1 loss impacts metabolic pathways related to cancer progression. Our data indicate that E2F1 binds to the promoter of several glutamine metabolism-related genes. Interestingly, the expression of genes in the glutamine metabolic pathway were increased in mouse embryonic fibroblasts (MEFs) lacking E2F1. In addition, we confirm that E2f1-/- MEFs are more efficient in metabolizing glutamine and producing glutamine-derived precursors for proliferation. Mechanistically, we observe a co-occupancy of E2F1 and MYC on glutamine metabolic promoters, increased MYC binding after E2F1 depletion and that silencing of MYC decreased the expression of glutamine-related genes in E2f1-/- MEFs. Analyses of transcriptomic profiles in 29 different human cancers identified uterine sarcoma that showed a negative correlation between E2F1 and glutamine metabolic genes. CRISPR/Cas9 knockout of E2F1 in the uterine sarcoma cell line SK-UT-1 confirmed elevated glutamine metabolic gene expression, increased proliferation and increased MYC binding to glutamine-related promoters upon E2F1 loss. Together, our data suggest a crucial role of E2F1 in energy metabolism and metabolic adaptation in uterine sarcoma cells.

Genome Med, auth.: group Reymond

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Sissy Bassani 1 2Jacqueline Chrast 1Giovanna Ambrosini 3 4Norine Voisin 1 5Frédéric Schütz 6Alfredo Brusco 7 8Fabio Sirchia 7 8 9 10Lydia Turban 11Susanna Schubert 11Rami Abou Jamra 11Jan-Ulrich Schlump 12Desiree DeMille 13Pinar Bayrak-Toydemir 14Gary Rex Nelson 14Kristen Nicole Wong 14Laura Duncan 15 16Mackenzie Mosera 15Christian Gilissen 17Lisenka E L M Vissers 17Rolph Pfundt 17Rogier Kersseboom 18Hilde Yttervik 19Geir Åsmund Myge Hansen 19Marie Falkenberg Smeland 20Kameryn M Butler 21Michael J Lyons 21Claudia M B Carvalho 22 23Chaofan Zhang 23James R Lupski 23 24 25 26Lorraine Potocki 23 26Leticia Flores-Gallegos 27Rodrigo Morales-Toquero 27Florence Petit 28Binnaz Yalcin 29Annabelle Tuttle 30Houda Zghal Elloumi 30Lane McCormick 31Mary Kukolich 31Oliver Klaas 32Judit Horvath 32Marcello Scala 33 34Michele Iacomino 34Francesca Operto 35Federico Zara 33 34Karin Writzl 36 37Aleš Maver 36Maria K Haanpää 38Pia Pohjola 38Harri Arikka 39Anneke J A Kievit 40Camilla Calandrini 40Christian Iseli 3 4Nicolas Guex 3 4Alexandre Reymond 41

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Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

Methods: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.

Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Plant Direct. auth.: Group Fankhauser

Pectin methylesterification state and cell wall mechanical properties contribute to neighbor proximity-induced hypocotyl growth in Arabidopsis

Fabien Sénéchal 1 2Sarah Robinson 3 4Evert Van Schaik 5 6Martine Trévisan 1Prashant Saxena 1 7Didier Reinhardt 5Christian Fankhauser 1

. 2024 Apr 21;8(4):e584.

 doi: 10.1002/pld3.584. eCollection 2024 Apr.


Plants growing with neighbors compete for light and consequently increase the growth of their vegetative organs to enhance access to sunlight. This response, called shade avoidance syndrome (SAS), involves photoreceptors such as phytochromes as well as phytochrome interacting factors (PIFs), which regulate the expression of growth-mediating genes. Numerous cell wall-related genes belong to the putative targets of PIFs, and the importance of cell wall modifications for enabling growth was extensively shown in developmental models such as dark-grown hypocotyl. However, the contribution of the cell wall in the growth of de-etiolated seedlings regulated by shade cues remains poorly established. Through analyses of mechanical and biochemical properties of the cell wall coupled with transcriptomic analysis of cell wall-related genes from previously published data, we provide evidence suggesting that cell wall modifications are important for neighbor proximity-induced elongation. Further analysis using loss-of-function mutants impaired in the synthesis and remodeling of the main cell wall polymers corroborated this. We focused on the cgr2cgr3 double mutant that is defective in methylesterification of homogalacturonan (HG)-type pectins. By following hypocotyl growth kinetically and spatially and analyzing the mechanical and biochemical properties of cell walls, we found that methylesterification of HG-type pectins was required to enable global cell wall modifications underlying neighbor proximity-induced hypocotyl growth. Collectively, our work suggests that plant competition for light induces changes in the expression of numerous cell wall genes to enable modifications in biochemical and mechanical properties of cell walls that contribute to neighbor proximity-induced growth.

Nucleic Acids Res, auth.: group Roignant

Comprehensive map of ribosomal 2′-O-methylation and C/D box snoRNAs in Drosophila melanogaster

Athena Sklias 1Sonia Cruciani 2Virginie Marchand 3Mariangela Spagnuolo 4Guillaume Lavergne 1Valérie Bourguignon 3Alessandro Brambilla 5René Dreos 1Steven J Marygold 6Eva Maria Novoa 2 7Yuri Motorin 3Jean-Yves Roignant 1 4

. 2024 Apr 12;52(6):2848-2864.

 doi: 10.1093/nar/gkae139.


During their maturation, ribosomal RNAs (rRNAs) are decorated by hundreds of chemical modifications that participate in proper folding of rRNA secondary structures and therefore in ribosomal function. Along with pseudouridine, methylation of the 2′-hydroxyl ribose moiety (Nm) is the most abundant modification of rRNAs. The majority of Nm modifications in eukaryotes are placed by Fibrillarin, a conserved methyltransferase belonging to a ribonucleoprotein complex guided by C/D box small nucleolar RNAs (C/D box snoRNAs). These modifications impact interactions between rRNAs, tRNAs and mRNAs, and some are known to fine tune translation rates and efficiency. In this study, we built the first comprehensive map of Nm sites in Drosophila melanogaster rRNAs using two complementary approaches (RiboMethSeq and Nanopore direct RNA sequencing) and identified their corresponding C/D box snoRNAs by whole-transcriptome sequencing. We de novo identified 61 Nm sites, from which 55 are supported by both sequencing methods, we validated the expression of 106 C/D box snoRNAs and we predicted new or alternative rRNA Nm targets for 31 of them. Comparison of methylation level upon different stresses show only slight but specific variations, indicating that this modification is relatively stable in D. melanogaster. This study paves the way to investigate the impact of snoRNA-mediated 2′-O-methylation on translation and proteostasis in a whole organism.