Recent CIG publications Archive

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EMBO Rep.: auth.: group Fajas

 2019 Aug 19:e47903. doi: 10.15252/embr.201947903. [Epub ahead of print]

Inter-organ communication: a gatekeeper for metabolic health.

Author information

1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Abstract

Multidirectional interactions between metabolic organs in the periphery and the central nervous system have evolved concomitantly with multicellular organisms to maintain whole-body energy homeostasis and ensure the organism’s adaptation to external cues. These interactions are altered in pathological conditions such as obesity and type 2 diabetes. Bioactive peptides and proteins, such as hormones and cytokines, produced by both peripheral organs and the central nervous system, are key messengers in this inter-organ communication. Despite the early discovery of the first hormones more than 100 years ago, recent studies taking advantage of novel technologies have shed light on the multiple ways used by cells in the body to communicate and maintain energy balance. This review briefly summarizes well-established concepts and focuses on recent advances describing how specific proteins and peptides mediate the crosstalk between gut, brain, and other peripheral metabolic organs in order to maintain energy homeostasis. Additionally, this review outlines how the improved knowledge about these inter-organ networks is helping us to redefine therapeutic strategies in an effort to promote healthy living and fight metabolic disorders and other diseases.

KEYWORDS:

energy homeostasis; inter-organ communication; metabolism; obesity

PMID: 31423716

 

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Cancer Res.: auth.: group Fajas

 2019 Aug 8. pii: canres.0708.2019. doi: 10.1158/0008-5472.CAN-19-0708. [Epub ahead of print]

CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival.

Abstract

Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor FLCN, regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacological inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation), and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncover a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells.

PMID: 31395606

 

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Proc Natl Acad Sci U S A.: co-auth.: GTF

 2019 Aug 2. pii: 201902148. doi: 10.1073/pnas.1902148116. [Epub ahead of print]

Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons.

Abstract

Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT (Peg3Ahr1Six6Nr2f2, and Prrx1) and MCH (Lmx1Gbx2, and Peg3) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigenic neuropeptide, QRFP, that might explain the metabolic syndrome in narcolepsy. The transcriptome results were used to develop protocols for the production of HCRT and MCH neurons from induced pluripotent stem cells and ascorbic acid was found necessary for HCRT and BMP7 for MCH cell differentiation. Our results provide a platform to understand the development and expression of HCRT and MCH and their multiple functions in health and disease.

KEYWORDS:

HCRT/OREXIN; MCH; Peg3; iPSC; transcription factor

PMID: 31375626

 

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Nat Commun.: auth.: group Reymond

 2019 Aug 1;10(1):3465. doi: 10.1038/s41467-019-11431-2.

Large-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis.

Collins SC1,2,3,4,5Mikhaleva A6Vrcelj K7Vancollie VE8Wagner C1,2,3,4Demeure N1,2,3,4Whitley H1,2,3,4Kannan M1,2,3,4Balz R6Anthony LFE8Edwards A9,10Moine H1,2,3,4White JK8Adams DJ8Reymond A6Lelliott CJ8Webber C7,11Yalcin B12,13,14,15,16.

Abstract

Brain morphogenesis is an important process contributing to higher-order cognition, however our knowledge about its biological basis is largely incomplete. Here we analyze 118 neuroanatomical parameters in 1,566 mutant mouse lines and identify 198 genes whose disruptions yield NeuroAnatomical Phenotypes (NAPs), mostly affecting structures implicated in brain connectivity. Groups of functionally similar NAP genes participate in pathways involving the cytoskeleton, the cell cycle and the synapse, display distinct fetal and postnatal brain expression dynamics and importantly, their disruption can yield convergent phenotypic patterns. 17% of human unique orthologues of mouse NAP genes are known loci for cognitive dysfunction. The remaining 83% constitute a vast pool of genes newly implicated in brain architecture, providing the largest study of mouse NAP genes and pathways. This offers a complementary resource to human genetic studies and predict that many more genes could be involved in mammalian brain morphogenesis.

PMID: 31371714

 

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Sci Transl Med.: group Wahli

 2019 Jul 24;11(502). pii: eaan5662. doi: 10.1126/scitranslmed.aan5662.

The gut microbiota influences skeletal muscle mass and function in mice.

Abstract

The functional interactions between the gut microbiota and the host are important for host physiology, homeostasis, and sustained health. We compared the skeletal muscle of germ-free mice that lacked a gut microbiota to the skeletal muscle of pathogen-free mice that had a gut microbiota. Compared to pathogen-free mouse skeletal muscle, germ-free mouse skeletal muscle showed atrophy, decreased expression of insulin-like growth factor 1, and reduced transcription of genes associated with skeletal muscle growth and mitochondrial function. Nuclear magnetic resonance spectrometry analysis of skeletal muscle, liver, and serum from germ-free mice revealed multiple changes in the amounts of amino acids, including glycine and alanine, compared to pathogen-free mice. Germ-free mice also showed reduced serum choline, the precursor of acetylcholine, the key neurotransmitter that signals between muscle and nerve at neuromuscular junctions. Reduced expression of genes encoding Rapsyn and Lrp4, two proteins important for neuromuscular junction assembly and function, was also observed in skeletal muscle from germ-free mice compared to pathogen-free mice. Transplanting the gut microbiota from pathogen-free mice into germ-free mice resulted in an increase in skeletal muscle mass, a reduction in muscle atrophy markers, improved oxidative metabolic capacity of the muscle, and elevated expression of the neuromuscular junction assembly genes Rapsyn and Lrp4 Treating germ-free mice with short-chain fatty acids (microbial metabolites) partly reversed skeletal muscle impairments. Our results suggest a role for the gut microbiota in regulating skeletal muscle mass and function in mice.

PMID: 31341063

 

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Nat Commun.: auth.: A. Reymond

 2019 Jul 24;10(1):3300. doi: 10.1038/s41467-019-10936-0.

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits.

Abstract

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.

PMID: 31341166