Recent CIG publications Archive

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Mol Biol Evol.: auth.: group Reymond

Mol Biol Evol. 2021 Aug 31;msab244. doi: 10.1093/molbev/msab244. Online ahead of print.

Alpha satellite insertion close to an ancestral centromeric region

Giuliana Giannuzzi 1 2 3Glennis A Logsdon 4Nicolas Chatron 2 5 6Danny E Miller 4 7Julie Reversat 5Katherine M Munson 4Kendra Hoekzema 4Marie-Noëlle Bonnet-Dupeyron 8Pierre-Antoine Rollat-Farnier 5 9Carl A Baker 4Damien Sanlaville 5 6Evan E Eichler 4 10Caroline Schluth-Bolard 5 6Alexandre Reymond 2

Abstract

Human centromeres are mainly composed of alpha satellite DNA hierarchically organized as higher-order repeats (HORs). Alpha satellite dynamics is shown by sequence homogenization in centromeric arrays and by its transfer to other centromeric locations, for example during the maturation of new centromeres. We identified during prenatal aneuploidy diagnosis by FISH a de novo insertion of alpha satellite DNA from the centromere of chromosome 18 (D18Z1) into cytoband 15q26. Although bound by CENP-B, this locus did not acquire centromeric functionality as demonstrated by lack of constriction and absence of CENP-A binding. The insertion was associated with a 2.8 kbp deletion and likely occurred in the paternal germline. The site was enriched in long terminal repeats (LTRs) and located ∼10 Mbp from the location where a centromere was ancestrally seeded and became inactive in the common ancestor of humans and apes 20-25 million years ago. Long-read mapping to the T2T-CHM13 human genome assembly revealed that the insertion derives from a specific region of chromosome 18 centromeric 12-mer HOR array in which the monomer size follows a regular pattern. The rearrangement did not directly disrupt any gene or predicted regulatory element and did not alter the methylation status of the surrounding region, consistent with the absence of phenotypic consequences in the carrier. This case demonstrates a likely rare but new class of structural variation that we name ‘alpha satellite insertion’. It also expands our knowledge on alphoid DNA dynamics and conveys the possibility that alphoid arrays can relocate near vestigial centromeric sites.

Read also the article published on l’Actu magazine regarding the Reymond’s lab research on human genetics, August 2021: http://www.genomyx.ch/a-reymond-was-in-lactu-magazine-regarding-his-lab-research-on-human-genetics-august-2021/

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Metabolites.: auth.: W.Wahli

Metabolites. 2021 Jul 30;11(8):502. doi: 10.3390/metabo11080502.

Roles of Estrogens in the Healthy and Diseased Oviparous Vertebrate Liver

Blandine Tramunt 1 2Alexandra Montagner 1Nguan Soon Tan 3Pierre Gourdy 1 2Hervé Rémignon 4 5Walter Wahli 3 5 6

Abstract

The liver is a vital organ that sustains multiple functions beneficial for the whole organism. It is sexually dimorphic, presenting sex-biased gene expression with implications for the phenotypic differences between males and females. Estrogens are involved in this sex dimorphism and their actions in the liver of several reptiles, fishes, amphibians, and birds are discussed. The liver participates in reproduction by producing vitellogenins (yolk proteins) and eggshell proteins under the control of estrogens that act via two types of receptors active either mainly in the cell nucleus (ESR) or the cell membrane (GPER1). Estrogens also control hepatic lipid and lipoprotein metabolisms, with a triglyceride carrier role for VLDL from the liver to the ovaries during oogenesis. Moreover, the activation of the vitellogenin genes is used as a robust biomarker for exposure to xenoestrogens. In the context of liver diseases, high plasma estrogen levels are observed in fatty liver hemorrhagic syndrome (FLHS) in chicken implicating estrogens in the disease progression. Fishes are also used to investigate liver diseases, including models generated by mutation and transgenesis. In conclusion, studies on the roles of estrogens in the non-mammalian oviparous vertebrate liver have contributed enormously to unveil hormone-dependent physiological and physiopathological processes.

Keywords: G protein-coupled estrogen receptor; estrogen receptors; growth hormone; liver diseases; nuclear receptors; oogenesis; sexual dimorphism; vitellogenin; xenoestrogens; yolk

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Am J Physiol Endocrinol Metab.: auth.: B.Thorens

Am J Physiol Endocrinol Metab. 2021 Aug 23. doi: 10.1152/ajpendo.00290.2021.

Mike Mueckler (1953-2021) – the father of the mammalian SLC2 glucose transporter family

David E James 1Bernard Thorens 2Affiliations expand

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Mol Metab.: co-auth.: B. Thorens

Mol Metab. 2021 Jul 26;101311. doi: 10.1016/j.molmet.2021.101311. Online ahead of print.

Ablation of glucokinase-expressing tanycytes impacts energy balance and increases adiposity in mice

Antoine Rohrbach 1Emilie Caron 2Rafik Dali 3Maxime Brunner 4Roxane Pasquettaz 5Irina Kolotuev 6Federico Santoni 4Bernard Thorens 5Fanny Langlet 7

Abstract

Objectives: Glucokinase (GCK) is critical for glucosensing. In rats, GCK is expressed in hypothalamic tanycytes and appears to play an essential role in feeding behavior. In this study, we investigated the distribution of GCK-expressing tanycytes in mice and their role in the regulation of energy balance.

Methods: In situ hybridization, reporter gene assay, and immunohistochemistry were used to assess GCK expression along the third ventricle in mice. To evaluate the impact of GCK-expressing tanycytes on arcuate neuron function and mouse physiology, Gck deletion along the ventricle was achieved using loxP/Cre recombinase technology in adult mice.

Results: GCK expression was low along the third ventricle but detectable in tanycytes facing the ventromedial arcuate nucleus from bregma -1.5 to -2.2. Gck deletion induced the death of this tanycyte subgroup through the activation of the BAD signaling pathway. The ablation of GCK-expressing tanycytes affected different aspects of energy balance, leading to an increase in adiposity in mice. This phenotype was systematically associated with a defect in NPY neuron function. In contrast, the regulation of glucose homeostasis was mostly preserved, except for glucoprivic responses.

Conclusions: This study describes an additional role for GCK in tanycyte biology and highlights the impact of tanycyte loss on the regulation of energy balance.

Keywords: Apoptosis; Energy Balance; Glucokinase; Glucose homeostasis; Hypothalamus; Tanycytes.

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Mol Cell. co-auth.: J-Y. Roignant

Mol Cell. 2021 Jul 20;S1097-2765(21)00503-7. doi: 10.1016/j.molcel.2021.06.023. Online ahead of print.

6 A RNA methylation regulates promoter- proximal pausing of RNA polymerase II

Junaid Akhtar 1Yoan Renaud 2Steffen Albrecht 3Yad Ghavi-Helm 4Jean-Yves Roignant 5Marion Silies 6Guillaume Junion 7Affiliations expand

Abstract

RNA polymerase II (RNAP II) pausing is essential to precisely control gene expression and is critical for development of metazoans. Here, we show that the m6A RNA modification regulates promoter-proximal RNAP II pausing in Drosophila cells. The m6A methyltransferase complex (MTC) and the nuclear reader Ythdc1 are recruited to gene promoters. Depleting the m6A MTC leads to a decrease in RNAP II pause release and in Ser2P occupancy on the gene body and affects nascent RNA transcription. Tethering Mettl3 to a heterologous gene promoter is sufficient to increase RNAP II pause release, an effect that relies on its m6A catalytic domain. Collectively, our data reveal an important link between RNAP II pausing and the m6A RNA modification, thus adding another layer to m6A-mediated gene regulation.

Keywords: RNA modification; RNA polymerase II pausing; m(6)A; transcription elongation; transcriptional checkpoint.

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Nat Metab.: co-auth.: B.Thorens

Nat Metab. 2021 Jun 28. doi: 10.1038/s42255-021-00420-9. Online ahead of print.

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes

Leonore Wigger # 1Marko Barovic # 2 3 4Andreas-David Brunner # 5Flavia Marzetta 1Eyke Schöniger 2 3 4Florence Mehl 1Nicole Kipke 2 3 4Daniela Friedland 2 3 4Frederic Burdet 1Camille Kessler 1Mathias Lesche 6Bernard Thorens 7Ezio Bonifacio 3 4 8Cristina Legido-Quigley 9 10Pierre Barbier Saint Hilaire 11Philippe Delerive 12Andreas Dahl 6Christian Klose 13Mathias J Gerl 13Kai Simons 13Daniela Aust 14 15Jürgen Weitz 16Marius Distler 16Anke M Schulte 17Matthias Mann 18Mark Ibberson 19Michele Solimena 20 21 22

Abstract

Most research on human pancreatic islets is conducted on samples obtained from normoglycaemic or diseased brain-dead donors and thus cannot accurately describe the molecular changes of pancreatic islet beta cells as they progress towards a state of deficient insulin secretion in type 2 diabetes (T2D). Here, we conduct a comprehensive multi-omics analysis of pancreatic islets obtained from metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum, from normoglycemia to T2D. We find that islet pools isolated from surgical samples by laser-capture microdissection display remarkably more heterogeneous transcriptomic and proteomic profiles in patients with diabetes than in non-diabetic controls. The differential regulation of islet gene expression is already observed in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive, but disharmonic, remodelling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or transdifferentiation stages in T2D. Furthermore, through integration of islet transcriptomics with preoperative blood plasma lipidomics, we define the relative importance of gene coexpression modules and lipids that are positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.