Review Curr Opin Genet Dev; auth.: group Roignant

Exploring pseudouridylation: dysregulation in disease and therapeutic potential

Maria Guillen-Angel 1Jean-Yves Roignant 2

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  • PMID: 38833893
  • . 2024 Jun 3:87:102210.
  •  doi: 10.1016/j.gde.2024.102210. Online ahead of print.

Free article


Pseudouridine (Ψ), the most abundant RNA modification, plays a role in pre-mRNA splicing, RNA stability, protein translation efficiency, and cellular responses to environmental stress. Dysregulation of pseudouridylation is linked to human diseases. This review explores recent insights into the role of RNA pseudouridylation alterations in human disorders and the therapeutic potential of Ψ. We discuss the impact of the reduction of Ψ levels in ribosomal, messenger, and transfer RNA in RNA processing, protein translation, and consequently its role in neurodevelopmental diseases and cancer. Furthermore, we review the success of N1-methyl-Ψ messenger RNA vaccines against COVID-19 and the development of RNA-guided pseudouridylation enzymes for treating genetic diseases caused by premature stop codons.

ReviewTrends Endocrinol Metab; co-auth.: W.Wahli

Increased hepatic gluconeogenesis and type 2 diabetes mellitus

Emma Barroso 1Javier Jurado-Aguilar 1Walter Wahli 2Xavier Palomer 1Manuel Vázquez-Carrera 3

. 2024 May 29:S1043-2760(24)00124-3.

Online ahead of print.


Abnormally increased hepatic gluconeogenesis is a significant contributor to hyperglycemia in the fasting state in patients with type 2 diabetes mellitus (T2DM) due to insulin resistance. Metformin, the most prescribed drug for the treatment of T2DM, is believed to exert its effect mainly by reducing hepatic gluconeogenesis. Here, we discuss how increased hepatic gluconeogenesis contributes to T2DM and we review newly revealed mechanisms underlying the attenuation of gluconeogenesis by metformin. In addition, we analyze the recent findings on new determinants involved in the regulation of gluconeogenesis, which might ultimately lead to the identification of novel and targeted treatment strategies for T2DM.

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.

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.