Recent CIG publications Archive

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Cells.: co-auth.: I.Lopez-Mejia and L.Fajas

Cells. 2022 Apr 20;11(9):1392. doi: 10.3390/cells11091392.

Glucose Starvation or Pyruvate Dehydrogenase Activation Induce a Broad, ERK5-Mediated, Metabolic Remodeling Leading to Fatty Acid Oxidation

Abrar Ul Haq Khan 1Hamideh Salehi 2Catherine Alexia 1Jose M Valdivielso 3Milica Bozic 3Isabel C Lopez-Mejia 4Lluis Fajas 4 5Sabine Gerbal-Chaloin 1Martine Daujat-Chavanieu 1 6Delphine Gitenay 1Martin Villalba 1 6 7Affiliations expand

Free PMC article

Abstract

Cells have metabolic flexibility that allows them to adapt to changes in substrate availability. Two highly relevant metabolites are glucose and fatty acids (FA), and hence, glycolysis and fatty acid oxidation (FAO) are key metabolic pathways leading to energy production. Both pathways affect each other, and in the absence of one substrate, metabolic flexibility allows cells to maintain sufficient energy production. Here, we show that glucose starvation or sustained pyruvate dehydrogenase (PDH) activation by dichloroacetate (DCA) induce large genetic remodeling to propel FAO. The extracellular signal-regulated kinase 5 (ERK5) is a key effector of this multistep metabolic remodeling. First, there is an increase in the lipid transport by expression of low-density lipoprotein receptor-related proteins (LRP), e.g., CD36, LRP1 and others. Second, an increase in the expression of members of the acyl-CoA synthetase long-chain (ACSL) family activates FA. Finally, the expression of the enzymes that catalyze the initial step in each cycle of FAO, i.e., the acyl-CoA dehydrogenases (ACADs), is induced. All of these pathways lead to enhanced cellular FAO. In summary, we show here that different families of enzymes, which are essential to perform FAO, are regulated by the signaling pathway, i.e., MEK5/ERK5, which transduces changes from the environment to genetic adaptations.

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Int J Mol Sci.: auth.: W.Wahli

Int J Mol Sci. 2022 Apr 30;23(9):5025. doi: 10.3390/ijms23095025.

PPARs as Key Mediators in the Regulation of Metabolism and Inflammation

Manuel Vázquez-Carrera 1 2Walter Wahli 3 4 5

Abstract

Nuclear receptors (NRs) form a large family of ligand-dependent transcription factors that control the expression of a multitude of genes involved in diverse, vital biological processes […].

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Sci Adv.: auth.: group Gambetta

Sci Adv. 2022 May 13;8(19):eabl8834. doi: 10.1126/sciadv.abl8834. Epub 2022 May 13.

Essential role of Cp190 in physical and regulatory boundary formation

Anjali Kaushal 1Julien Dorier 2Bihan Wang 1Giriram Mohana 1Michael Taschner 3Pascal Cousin 1Patrice Waridel 4Christian Iseli 2Anastasiia Semenova 1Simon Restrepo 5Nicolas Guex 2Erez Lieberman Aiden 6 7 8 9Maria Cristina Gambetta 1

Abstract

Boundaries in animal genomes delimit contact domains with enhanced internal contact frequencies and have debated functions in limiting regulatory cross-talk between domains and guiding enhancers to target promoters. Most mammalian boundaries form by stalling of chromosomal loop-extruding cohesin by CTCF, but most Drosophila boundaries form CTCF independently. However, how CTCF-independent boundaries form and function remains largely unexplored. Here, we assess genome folding and developmental gene expression in fly embryos lacking the ubiquitous boundary-associated factor Cp190. We find that sequence-specific DNA binding proteins such as CTCF and Su(Hw) directly interact with and recruit Cp190 to form most promoter-distal boundaries. Cp190 is essential for early development and prevents regulatory cross-talk between specific gene loci that pattern the embryo. Cp190 was, in contrast, dispensable for long-range enhancer-promoter communication at tested loci. Cp190 is thus currently the major player in fly boundary formation and function, revealing that diverse mechanisms evolved to partition genomes into independent regulatory domains.

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FASEB J.: co-auth.: W.Wahli

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R5306.

The Loss of PPARα in Adipocytes Induces Lipogenesis via the PASK-SREBP1 Signaling Axis

Zachary A Kipp 1Mei Xu 1Frederique Yiannikouris 1 2Andrew Morris 3 4Donald Stec 5Walter Wahli 6 7 8David Stec 9Terry Hinds Jr 1 2 10

Abstract

PPARα is a nuclear receptor and a key player in regulating adiposity by activating b-oxidation while inhibiting de novo lipogenesis within the liver. Its role in extrahepatic tissues is currently unknown. Therefore, we established the first adipose-specific PPARα knockout (PparaFatKO ) mice to determine the signaling position of PPARα in adipose tissue expansion and adipocyte hypertrophy that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male PparaFatKO animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) (p=0.0091) and brown adipose tissue (BAT) (p=0.0031) with HFD compared to littermates. No changes in adiposity were observed in female mice compared to littermate controls. Lipidomics analysis of iWAT via liquid chromatography-mass spectrometry (LC-MS) showed that PparaFatKO males had an increase in cholesterol esters. Interrogation of the signaling mechanisms with the loss of PPARα in adipocytes showed that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) had more of the mature form present in the KO males and its target genes were higher, which might be due to the significantly (p=0.009) elevated expression of the Per-Arnt-Sim Kinase (PASK), a kinase that activates SREBP-1. The hyperactivity of the PASK-SREBP-1 axis significantly (p<0.05) increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl-Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1, Abcg1, and Abca1). Hence, we have uncovered a new signaling paradigm, the PASK-SREBP-1 axis in adipocytes, that drives lipogenesis, which PPARα inhibits. Our results demonstrate the first adipose-specific actions for PPARα in protecting against lipogenesis and cholesterol ester accumulation that leads to adipocyte hypertrophy in obesity.

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Cell Metab.: co-auth.: PAF

Cell Metab. 2022 Apr 18;S1550-4131(22)00127-9. doi: 10.1016/j.cmet.2022.03.013. Online ahead of print.

The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function

Mathias Wenes 1Alison Jaccard 2Tania Wyss 3Noelia Maldonado-Pérez 4Shao Thing Teoh 5Anouk Lepez 6Fabrice Renaud 3Fabien Franco 2Patrice Waridel 7Céline Yacoub Maroun 3Benjamin Tschumi 3Nina Dumauthioz 3Lianjun Zhang 8Alena Donda 3Francisco Martín 4Denis Migliorini 9Sophia Y Lunt 10Ping-Chih Ho 2Pedro Romero 11

Abstract

Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.

Keywords: T cell memory; chimeric antigen receptor T cell therapy; immunometabolism; mitochondrial pyruvate carrier; tumor-infiltrating lymphocyte metabolism.

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CRISPR 2022: registration and abstract submission are open – Deadline 02.08.2022

The CRISPR and Beyond: Perturbations at Scale to Understand Genomes (28-30 September 2022) hybrid conference is open for registration and abstract submissions.

The fourth meeting in this series will focus on how advances in gene-editing technology and DNA synthesis are making it possible to modulate genomes with ease.

Join a community of international biomedical researchers to explore the emerging technologies and models (including computational approaches) that are enabling enhanced precision medicine for heritable diseases and cancer treatment.

Hear from our expert-speakers on the functional implications of natural and disease-related human genetic variation, and how this affects the application of CRISPR/Cas-based functional genomics in identifying new drug targets.

Discuss a variety of exciting topics:
– Emerging technologies and models
– Computational models
– Controlling transcription
– Protein engineering
– Highly parallel readouts
– Precision editing
– Functional genomics in drug discovery (panel discussion)

If you have research to share, we are accepting abstract submissions on any of these key areas.

Receive feedback from – and network with – experts in the fields of high throughput screening, genome engineering, and variant effect interpretation; forming connections with the potential to advance your research, and your career.

Register here: https://email.wellcomeconnectingscience.org/6Y2C-52PG-1GUFG5-2SAJI-1/c.aspx

Key dates:
Abstract and bursary deadline: 2 August 2022
Registration deadline (in-person): 30 August 2022
Registration deadline (virtual): 20 September 2022

Scientific committee:
John DoenchBroad Institute of MIT and Harvard, USA
Jolanda van LeeuwenUniversity of Lausanne, Switzerland
Leopold PartsWellcome Sanger Institute, UK
Lea StaritaUniversity of Washington, USA