Recent CIG publications Archive

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

• PMID: 34464971
• DOI: 10.1093/molbev/msab244

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/

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 ¹, Bernard Thorens ²Affiliations expand

• PMID: 34423681
• DOI: 10.1152/ajpendo.00290.2021

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 ¹, Emilie Caron ², Rafik Dali ³, Maxime Brunner ⁴, Roxane Pasquettaz ⁵, Irina Kolotuev ⁶, Federico Santoni ⁴, Bernard Thorens ⁵, Fanny 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.

• PMID: 34325016
• DOI: 10.1016/j.molmet.2021.101311

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

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

Junaid Akhtar ¹, Yoan Renaud ², Steffen Albrecht ³, Yad Ghavi-Helm ⁴, Jean-Yves Roignant ⁵, Marion Silies ⁶, Guillaume 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.

• PMID: 34297910
• DOI: 10.1016/j.molcel.2021.06.023

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

• PMID: 34183850
• DOI: 10.1038/s42255-021-00420-9