Recent CIG publications Archive


Am J Hum Genet.: auth.: group Reymond

Am J Hum Genet. 2021 May 6;108(5):857-873. doi: 10.1016/j.ajhg.2021.04.001.

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Norine Voisin 1Rhonda E Schnur 2Sofia Douzgou 3Susan M Hiatt 4Cecilie F Rustad 5Natasha J Brown 6Dawn L Earl 7Boris Keren 8Olga Levchenko 9Sinje Geuer 10Sarah Verheyen 11Diana Johnson 12Yuri A Zarate 13Miroslava Hančárová 14David J Amor 15E Martina Bebin 16Jasmin Blatterer 11Alfredo Brusco 17Gerarda Cappuccio 18Joel Charrow 19Nicolas Chatron 20Gregory M Cooper 4Thomas Courtin 8Elena Dadali 9Julien Delafontaine 21Ennio Del Giudice 22Martine Doco 23Ganka Douglas 24Astrid Eisenkölbl 25Tara Funari 24Giuliana Giannuzzi 1Ursula Gruber-Sedlmayr 26Nicolas Guex 27Delphine Heron 8Øystein L Holla 28Anna C E Hurst 29Jane Juusola 24David Kronn 30Alexander Lavrov 9Crystle Lee 31Séverine Lorrain 32Else Merckoll 33Anna Mikhaleva 1Jennifer Norman 34Sylvain Pradervand 35Darina Prchalová 14Lindsay Rhodes 24Victoria R Sanders 19Zdeněk Sedláček 14Heidelis A Seebacher 11Elizabeth A Sellars 13Fabio Sirchia 36Toshiki Takenouchi 37Akemi J Tanaka 38Heidi Taska-Tench 19Elin Tønne 5Kristian Tveten 28Giuseppina Vitiello 22Markéta Vlčková 14Tomoko Uehara 37Caroline Nava 8Binnaz Yalcin 39Kenjiro Kosaki 37Dian Donnai 3Stefan Mundlos 10Nicola Brunetti-Pierri 18Wendy K Chung 38Alexandre Reymond 40Affiliations expand


The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

Keywords: AFF3; AFF4; horseshoe kidney; intellectual disability; mesomelic dysplasia.

The UNIL web magasine L’Actu published an interview of Prof. A. Reymond and Dr N.Voisin regarding this article:


Nat Commun.: co-auth.: L.Michalik

Nat Commun. 2021 May 5;12(1):2538. doi: 10.1038/s41467-021-22764-2.

PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions

Giuseppe Ercolano 1 2Alejandra Gomez-Cadena 1 2Nina Dumauthioz 3Giulia Vanoni 3Mario Kreutzfeldt 4Tania Wyss 3Liliane Michalik 5Romain Loyon 6 7Angela Ianaro 8Ping-Chih Ho 3Christophe Borg 6 7Manfred Kopf 9Doron Merkler 4Philippe Krebs 10Pedro Romero 3Sara Trabanelli 1 2Camilla Jandus 11 12Affiliations expand

Free article


Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.


Cancers (Basel).: auth.: W.Wahli

Cancers (Basel). 2021 Apr 29;13(9):2153. doi: 10.3390/cancers13092153.

PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal-Epithelial Crosstalk and Carcinogenesis

Hong Sheng Cheng 1Yun Sheng Yip 1Eldeen Kai Yi Lim 2Walter Wahli 1 3 4Nguan Soon Tan 1 2Affiliations expand

Free article


Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.

Keywords: cancer-associated adipocyte; cancer-associated fibroblast; metabolic reprogramming; peroxisome proliferation-activated receptor; tumor-associated macrophage.


Front Mol Biosci.: co-auth.: M.Quadroni

Front Mol Biosci. 2021 Apr 15;8:653073. doi: 10.3389/fmolb.2021.653073. eCollection 2021.

Bacterial Hsp90 Facilitates the Degradation of Aggregation-Prone Hsp70-Hsp40 Substrates

Bruno Fauvet 1Andrija Finka 2Marie-Pierre Castanié-Cornet 3Anne-Marie Cirinesi 3Pierre Genevaux 3Manfredo Quadroni 4Pierre Goloubinoff 1Affiliations expand

Free PMC article


In eukaryotes, the 90-kDa heat shock proteins (Hsp90s) are profusely studied chaperones that, together with 70-kDa heat shock proteins (Hsp70s), control protein homeostasis. In bacteria, however, the function of Hsp90 (HtpG) and its collaboration with Hsp70 (DnaK) remains poorly characterized. To uncover physiological processes that depend on HtpG and DnaK, we performed comparative quantitative proteomic analyses of insoluble and total protein fractions from unstressed wild-type (WT) Escherichia coli and from knockout mutants ΔdnaKdnaJ (ΔKJ), ΔhtpG (ΔG), and ΔdnaKdnaJΔhtpG (ΔKJG). Whereas the ΔG mutant showed no detectable proteomic differences with wild-type, ΔKJ expressed more chaperones, proteases and ribosomes and expressed dramatically less metabolic and respiratory enzymes. Unexpectedly, we found that the triple mutant ΔKJG showed higher levels of metabolic and respiratory enzymes than ΔKJ, suggesting that bacterial Hsp90 mediates the degradation of aggregation-prone Hsp70-Hsp40 substrates. Further in vivo experiments suggest that such Hsp90-mediated degradation possibly occurs through the HslUV protease.

Keywords: DnaJ; DnaK; HslV; HtpG; chaperones; proteostasis.


Diabetes.: auth.: group Thorens

Diabetes. 2021 Apr 21;db201121. doi: 10.2337/db20-1121. Online ahead of print.

Fgf15 neurons of the dorsomedial hypothalamus control glucagon secretion and hepatic gluconeogenesis

Alexandre Picard 1Salima Metref 1David Tarussio 1Wanda Dolci 1Xavier Berney 1Sophie Croizier 1Gwenaël Labouebe 1Bernard Thorens 2


The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this gluco-regulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus, as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15CretdTomato mice and their use to further characterize these neurons. We showed that they were glutamatergic and comprised glucose inhibited and glucose excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the dorsomedial hypothalamus participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally-induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia.


Gut.: co-auth.: W.Wahli

Gut. 2021 Apr 26;gutjnl-2020-323323. doi: 10.1136/gutjnl-2020-323323. Online ahead of print.

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

Sarra Smati 1 2Arnaud Polizzi 1Anne Fougerat 1Sandrine Ellero-Simatos 1Yuna Blum 3 4Yannick Lippi 1Marion Régnier 1Alexia Laroyenne 1Marine Huillet 1Muhammad Arif 5Cheng Zhang 5Frederic Lasserre 1Alain Marrot 1Talal Al Saati 6JingHong Wan 7 8Caroline Sommer 1Claire Naylies 1Aurelie Batut 2Celine Lukowicz 1Tiffany Fougeray 1Blandine Tramunt 2Patricia Dubot 9 10Lorraine Smith 1Justine Bertrand-Michel 2Nathalie Hennuyer 11Jean-Philippe Pradere 2Bart Staels 11Remy Burcelin 2Françoise Lenfant 2Jean-François Arnal 2Thierry Levade 9 10Laurence Gamet-Payrastre 1Sandrine Lagarrigue 12Nicolas Loiseau 1Sophie Lotersztajn 7 8Catherine Postic 13Walter Wahli 1 14 15Christophe Bureau 16Maeva Guillaume 16Adil Mardinoglu 5 17Alexandra Montagner 2Pierre Gourdy # 18 19Hervé Guillou # 20Affiliations expand


Objective: We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans.

Design: Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver.

Results: The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα.

Conclusions: These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.