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6. The transcriptional landscape of age in human peripheral blood.

Author

Peters, Marjolein J, Joehanes, Roby, Pilling, Luke C, Schurmann, Claudia, Conneely, Karen N, Powell, Joseph, Reinmaa, Eva, Sutphin, George L, Zhernakova, Alexandra, Schramm, Katharina, Wilson, Yana A, Kobes, Sayuko, Tukiainen, Taru, NABEC/UKBEC Consortium, Ramos, Yolande F, Göring, Harald HH, Fornage, Myriam, Liu, Yongmei, Gharib, Sina A, Stranger, Barbara E, De Jager, Philip L, Aviv, Abraham, Levy, Daniel, Murabito, Joanne M, Munson, Peter J, Huan, Tianxiao, Hofman, Albert, Uitterlinden, André G, Rivadeneira, Fernando, van Rooij, Jeroen, Stolk, Lisette, Broer, Linda, Verbiest, Michael MPJ, Jhamai, Mila, Arp, Pascal, Metspalu, Andres, Tserel, Liina, Milani, Lili, Samani, Nilesh J, Peterson, Pärt, Kasela, Silva, Codd, Veryan, Peters, Annette, Ward-Caviness, Cavin K, Herder, Christian, Waldenberger, Melanie, Roden, Michael, Singmann, Paula, Zeilinger, Sonja, Illig, Thomas, Homuth, Georg, Grabe, Hans-Jörgen, Völzke, Henry, Steil, Leif, Kocher, Thomas, Murray, Anna, Melzer, David, Yaghootkar, Hanieh, Bandinelli, Stefania, Moses, Eric K, Kent, Jack W, Curran, Joanne E, Johnson, Matthew P, Williams-Blangero, Sarah, Westra, Harm-Jan, McRae, Allan F, Smith, Jennifer A, Kardia, Sharon LR, Hovatta, Iiris, Perola, Markus, Ripatti, Samuli, Salomaa, Veikko, Henders, Anjali K, Martin, Nicholas G, Smith, Alicia K, Mehta, Divya, Binder, Elisabeth B, Nylocks, K Maria, Kennedy, Elizabeth M, Klengel, Torsten, Ding, Jingzhong, Suchy-Dicey, Astrid M, Enquobahrie, Daniel A, Brody, Jennifer, Rotter, Jerome I, Chen, Yii-Der I, Houwing-Duistermaat, Jeanine, Kloppenburg, Margreet, Slagboom, P Eline, Helmer, Quinta, den Hollander, Wouter, Bean, Shannon, Raj, Towfique, Bakhshi, Noman, Wang, Qiao Ping, Oyston, Lisa J, Psaty, Bruce M, Tracy, Russell P, Montgomery, Grant W, and Turner, Stephen T

Subjects
NABEC/UKBEC Consortium, Humans, Gene Expression Profiling, DNA Methylation, Aging, European Continental Ancestry Group, Transcriptome, Biomarkers
Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015

8. Natural compounds as obesity pharmacotherapies.

Author

Zhao, Xin‐Yuan, Wang, Ji‐Qiu, Neely, G. Gregory, Shi, Yan‐Chuan, and Wang, Qiao‐Ping

Abstract

Obesity has become a serious global public health problem, affecting over 988 million people worldwide. Nevertheless, current pharmacotherapies have proven inadequate. Natural compounds have garnered significant attention due to their potential antiobesity effects. Over the past three decades, ca. 50 natural compounds have been evaluated for the preventive and/or therapeutic effects on obesity in animals and humans. However, variations in the antiobesity efficacies among these natural compounds have been substantial, owing to differences in experimental designs, including variations in animal models, dosages, treatment durations, and administration methods. The feasibility of employing these natural compounds as pharmacotherapies for obesity remained uncertain. In this review, we systematically summarized the antiobesity efficacy and mechanisms of action of each natural compound in animal models. This comprehensive review furnishes valuable insights for the development of antiobesity medications based on natural compounds. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Branched-chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control

Author

Solon-Biet, Samantha M., Cogger, Victoria C., Pulpitel, Tamara, Wahl, Devin, Clark, Ximonie, Bagley, Elena E., Gregoriou, Gabrielle C., Senior, Alistair M., Wang, Qiao-Ping, Brandon, Amanda E., Perks, Ruth, O’Sullivan, John, Koay, Yen Chin, Bell-Anderson, Kim, Kebede, Melkam, Yau, Belinda, Atkinson, Clare, Svineng, Gunbjorg, Dodgson, Tim, Wali, Jibran A., Piper, Matthew D. W., Juricic, Paula, Partridge, Linda, Rose, Adam J., Raubenheimer, David, Cooney, Gregory J., Le Couteur, David G., and Simpson, Stephen J.

Published
2019
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11. Integrating genome-wide CRISPR screens and in silico drug profiling for targeted antidote development

Author

Wang, Bei, Xu, Yu, Wan, Arabella H., Wan, Guohui, and Wang, Qiao-Ping

Abstract

Numerous toxins threaten humans, but specific antidotes are unavailable for most of them. Although CRISPR screening has aided the discovery of the mechanisms of some toxins, developing targeted antidotes remains a significant challenge. Recently, we established a systematic framework to develop antidotes by combining the identification of novel drug targets by using a genome-wide CRISPR screen with a virtual screen of drugs approved by the US Food and Drug Administration. This approach allows for a comprehensive understanding of toxin mechanisms at the whole-genome level and facilitates the identification of promising antidote drugs targeting specific molecules. Here, we present step-by-step instructions for executing genome-scale CRISPR–Cas9 knockout screens of toxins in HAP1 cells. We also provide detailed guidance for conducting an in silico drug screen and an in vivo drug validation. By using this protocol, it takes ~4 weeks to perform the genome-scale screen, 4 weeks for sequencing and data analysis, 4 weeks to validate candidate genes, 1 week for the virtual screen and 2 weeks for in vitro drug validation. This framework has the potential to accelerate the development of antidotes for a wide range of toxins and can rapidly identify promising drug candidates that are already known to be safe and effective. This could lead to the development of new antidotes much more quickly than traditional methods, protecting lives from diverse toxins and advancing human health.

Published
2024
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12. Global redox proteome and phosphoproteome analysis reveals redox switch in Akt

Author

Su, Zhiduan, Burchfield, James G., Yang, Pengyi, Humphrey, Sean J., Yang, Guang, Francis, Deanne, Yasmin, Sabina, Shin, Sung-Young, Norris, Dougall M., Kearney, Alison L., Astore, Miro A., Scavuzzo, Jonathan, Fisher-Wellman, Kelsey H., Wang, Qiao-Ping, Parker, Benjamin L., Neely, G. Gregory, Vafaee, Fatemeh, Chiu, Joyce, Yeo, Reichelle, Hogg, Philip J., Fazakerley, Daniel J., Nguyen, Lan K., Kuyucak, Serdar, and James, David E.

Published
2019
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15. The combined effect of metformin and mirabegron on diet‐induced obesity

Author

Zhao, Xin‐Yuan, primary, Liu, Ying, additional, Zhang, Xuan, additional, Zhao, Ben‐Chi, additional, Burley, George, additional, Yang, Zhi‐Can, additional, Luo, Yi, additional, Li, An‐Qi, additional, Zhang, Ruo‐Xin, additional, Liu, Zhi‐Ying, additional, Shi, Yan‐Chuan, additional, and Wang, Qiao‐Ping, additional

Published
2023
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18. Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism

Author

Valsesia, Armand, Wang, Qiao-Ping, Gheldof, Nele, Carayol, Jérôme, Ruffieux, Hélène, Clark, Teleri, Shenton, Victoria, Oyston, Lisa J., Lefebvre, Gregory, Metairon, Sylviane, Chabert, Christian, Walter, Ondine, Mironova, Polina, Lau, Paulina, Descombes, Patrick, Viguerie, Nathalie, Langin, Dominique, Harper, Mary-Ellen, Astrup, Arne, Saris, Wim H., Dent, Robert, Neely, Greg G., and Hager, Jörg

Published
2019
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23. dSec16 Acting in Insulin-like Peptide Producing Cells Controls Energy Homeostasis in Drosophila.

Author

Zhang, Ruo-Xin, Li, Sha-Sha, Li, An-Qi, Liu, Zhi-Ying, Neely, G Gregory, and Wang, Qiao-Ping

Subjects
PEPTIDES, GENOME-wide association studies, DROSOPHILA, FOOD consumption, ENTEROENDOCRINE cells, ENERGY metabolism
Abstract

Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. However, the majority of them have not been functionally validated. SEC16B has been identified in multiple obesity GWASs but its physiological role in energy homeostasis remains unknown. Here, we use Drosophila to determine the physiological functions of dSec16 in energy metabolism. Our results showed that global RNAi of dSec16 increased food intake and triglyceride (TAG) levels. Furthermore, this TAG increase was observed in flies with a specific RNAi of dSec16 in insulin-like peptide producing cells (IPCs) with an alteration of endocrine peptides. Together, our study demonstrates that dSec16 acting in IPCs controls energy balance and advances the molecular understanding of obesity. [ABSTRACT FROM AUTHOR]

Published
2023
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25. N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis

Author

Lin, Ziyou, Wan, Arabella H., Sun, Lei, Liang, Heng, Niu, Yi, Deng, Yuan, Yan, Shijia, Wang, Qiao-Ping, Bu, Xianzhang, Zhang, Xiaolei, Hu, Kunhua, Wan, Guohui, and He, Weiling

Abstract

N6-methyladenosine (m6A) is the most pervasive RNA modification and is recognized as a novel epigenetic regulation in RNA metabolism. Although the m6A modification involves various physiological processes, its roles in drug resistance in colorectal cancer (CRC) still remain unknown. We analyzed the RNA expression profile of m6A/A (%) with MRM mass spectrometry in human 5-fluorouracil (5-FU)-resistant CRC tissues, and used the m6A RNA immunoprecipitation assay to validate the m6A-regulated target. Our results have shown that the m6A demethylase FTO was up-regulated in human primary and 5-FU-resistant CRC. Depletion of FTO decreased cell growth, colony formation and metastasis in 5-FU-resistant CRC cells in vitroand in vivo. Mechanistically, we identified SIVA1, a critical apoptotic gene, as a key downstream target of the FTO-mediated m6A demethylation. The m6A demethylation of SIVA1 at the CDS region induced its mRNA degradation via a YTHDF2-dependent mechanism. The SIVA1 levels were negatively correlated with the FTO levels in clinical CRC tissues. Notably, inhibition of FTO significantly reduced the tolerance of 5-FU in 5-FU-resistant CRC cells via the FTO-SIVA1 axis, whereas SIVA1-depletion could restore the m6A-dependent 5-FU sensitivity in CRC cells. In summary, our findings demonstrate a critical role of FTO as an m6A demethylase enhancing chemo-resistance in CRC cells, and suggest that FTO inhibition may restore the sensitivity of chemo-resistant CRC cells to 5-FU.

Published
2023
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30. Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons

Author

Khoury, Samar, primary, Wang, Qiao-Ping, additional, Parisien, Marc, additional, Gris, Pavel, additional, Bortsov, Andrey V, additional, Linnstaedt, Sarah D, additional, McLean, Samuel A, additional, Tungate, Andrew S, additional, Sofer, Tamar, additional, Lee, Jiwon, additional, Louie, Tin, additional, Redline, Susan, additional, Kaunisto, Mari Anneli, additional, Kalso, Eija A, additional, Munter, Hans Markus, additional, Nackley, Andrea G, additional, Slade, Gary D, additional, Smith, Shad B, additional, Zaykin, Dmitri V, additional, Fillingim, Roger B, additional, Ohrbach, Richard, additional, Greenspan, Joel D, additional, Maixner, William, additional, Neely, G Gregory, additional, and Diatchenko, Luda, additional

Published
2020
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32. Identification of ALK in Thinness

Author

Orthofer, Michael, primary, Valsesia, Armand, additional, Mägi, Reedik, additional, Wang, Qiao-Ping, additional, Kaczanowska, Joanna, additional, Kozieradzki, Ivona, additional, Leopoldi, Alexandra, additional, Cikes, Domagoj, additional, Zopf, Lydia M., additional, Tretiakov, Evgenii O., additional, Demetz, Egon, additional, Hilbe, Richard, additional, Boehm, Anna, additional, Ticevic, Melita, additional, Nõukas, Margit, additional, Jais, Alexander, additional, Spirk, Katrin, additional, Clark, Teleri, additional, Amann, Sabine, additional, Lepamets, Maarja, additional, Neumayr, Christoph, additional, Arnold, Cosmas, additional, Dou, Zhengchao, additional, Kuhn, Volker, additional, Novatchkova, Maria, additional, Cronin, Shane J.F., additional, Tietge, Uwe J.F., additional, Müller, Simone, additional, Pospisilik, J. Andrew, additional, Nagy, Vanja, additional, Hui, Chi-Chung, additional, Lazovic, Jelena, additional, Esterbauer, Harald, additional, Hagelkruys, Astrid, additional, Tancevski, Ivan, additional, Kiefer, Florian W., additional, Harkany, Tibor, additional, Haubensak, Wulf, additional, Neely, G. Gregory, additional, Metspalu, Andres, additional, Hager, Jorg, additional, Gheldof, Nele, additional, and Penninger, Josef M., additional

Published
2020
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33. PGC1α Controls Sucrose Taste Sensitization in Drosophila

Author

Wang, Qiao-Ping, primary, Lin, Yong Qi, additional, Lai, Mei-Ling, additional, Su, Zhiduan, additional, Oyston, Lisa J., additional, Clark, Teleri, additional, Park, Scarlet J., additional, Khuong, Thang M., additional, Lau, Man-Tat, additional, Shenton, Victoria, additional, Shi, Yan-Chuan, additional, James, David E., additional, Ja, William W., additional, Herzog, Herbert, additional, Simpson, Stephen J., additional, and Neely, G. Gregory, additional

Published
2020
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35. Regulation of Burkholderia cenocepaciavirulence by the fatty acyl-CoA ligase DsfR as a response regulator of quorum sensing signal

Author

Li, Xia, Song, Shihao, Kong, Xiaohan, Chen, Xiayu, Zhao, Zhuoxian, Lin, Zizi, Jia, Yantao, Zhang, Yong, Luo, Hai-Bin, Wang, Qiao-Ping, Zhang, Lian-Hui, Qian, Wei, and Deng, Yinyue

Abstract

Quorum sensing (QS) is a cell-to-cell communication mechanism mediated by small diffusible signaling molecules. Previous studies showed that RpfR controls Burkholderia cenocepaciavirulence as a cis-2-dodecenoic acid (BDSF) QS signal receptor. Here, we report that the fatty acyl-CoA ligase DsfR (BCAM2136), which efficiently catalyzes in vitrosynthesis of lauryl-CoA and oleoyl-CoA from lauric acid and oleic acid, respectively, acts as a global transcriptional regulator to control B. cenocepaciavirulence by sensing BDSF. We show that BDSF binds to DsfR with high affinity and enhances the binding of DsfR to the promoter DNA regions of target genes. Furthermore, we demonstrate that the homolog of DsfR in B. lata, RS02960, binds to the target gene promoter, and perception of BDSF enhances the binding activity of RS02960. Together, these results provide insights into the evolved unusual functions of DsfR that control bacterial virulence as a response regulator of QS signal.

Published
2024
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38. RagC phosphorylation autoregulates mTOR complex 1

Author

Yang, Guang, primary, Humphrey, Sean J, additional, Murashige, Danielle S, additional, Francis, Deanne, additional, Wang, Qiao‐Ping, additional, Cooke, Kristen C, additional, Neely, G Gregory, additional, and James, David E, additional

Published
2018
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39. Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice

Author

Wahl, Devin, primary, Solon-Biet, Samantha M., additional, Wang, Qiao-Ping, additional, Wali, Jibran A., additional, Pulpitel, Tamara, additional, Clark, Ximonie, additional, Raubenheimer, David, additional, Senior, Alistair M., additional, Sinclair, David A., additional, Cooney, Gregory J., additional, de Cabo, Rafael, additional, Cogger, Victoria C., additional, Simpson, Stephen J., additional, and Le Couteur, David G., additional

Published
2018
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40. Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons.

Author

Khoury, Samar, Wang, Qiao-Ping, Parisien, Marc, Gris, Pavel, Bortsov, Andrey V, Linnstaedt, Sarah D, McLean, Samuel A, Tungate, Andrew S, Sofer, Tamar, Lee, Jiwon, Louie, Tin, Redline, Susan, Kaunisto, Mari Anneli, Kalso, Eija A, Munter, Hans Markus, Nackley, Andrea G, Slade, Gary D, Smith, Shad B, Zaykin, Dmitri V, and Fillingim, Roger B

Published
2021
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43. A simple high throughput assay to evaluate water consumption in the fruit fly

Author

Lau, Man-Tat, primary, Lin, Yong Qi, additional, Kisling, Stefan, additional, Cotterell, James, additional, Wilson, Yana A., additional, Wang, Qiao-Ping, additional, Khuong, Thang M., additional, Bakhshi, Noman, additional, Cole, Tiffany A., additional, Oyston, Lisa J., additional, Cole, Adam R., additional, and Neely, G. Gregory, additional

Published
2017
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46. RagC phosphorylation autoregulates mTOR complex 1.

Author

Yang, Guang, Humphrey, Sean J, Murashige, Danielle S, Francis, Deanne, Wang, Qiao‐Ping, Cooke, Kristen C, Neely, G Gregory, and James, David E

Subjects
PHOSPHORYLATION, RAPAMYCIN, CELL growth, CELL proliferation, HETERODIMERS
Abstract

The mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) controls cell growth, proliferation, and metabolism in response to diverse stimuli. Two major parallel pathways are implicated in mTORC1 regulation including a growth factor‐responsive pathway mediated via TSC2/Rheb and an amino acid‐responsive pathway mediated via the Rag GTPases. Here, we identify and characterize three highly conserved growth factor‐responsive phosphorylation sites on RagC, a component of the Rag heterodimer, implicating cross talk between amino acid and growth factor‐mediated regulation of mTORC1. We find that RagC phosphorylation is associated with destabilization of mTORC1 and is essential for both growth factor and amino acid‐induced mTORC1 activation. Functionally, RagC phosphorylation suppresses starvation‐induced autophagy, and genetic studies in Drosophila reveal that RagC phosphorylation plays an essential role in regulation of cell growth. Finally, we identify mTORC1 as the upstream kinase of RagC on S21. Our data highlight the importance of RagC phosphorylation in its function and identify a previously unappreciated auto‐regulatory mechanism of mTORC1 activity. Synopsis: The mechanistic target of rapamycin complex1 (mTORC1) controls cell growth, proliferation and metabolism in response to diverse stimuli. This study identifies a new auto‐regulatory branch of mTORC1 signaling involving phosphorylation of the Rag GTPase RagC by mTORC1, which is required for full mTORC1 activation by growth factors and amino acids. Growth factors and amino acids stimulate mTORC1‐mediated phosphorylation of RagC.RagC phosphorylation is essential for both growth factor‐ and amino acid‐induced mTORC1 activity.RagC phosphorylation is required for mTORC1 regulation of cell size and autophagy in vitro and in Drosophila wing discs.RagC phosphorylation is associated with activation and concomitant destabilization of mTORC1. Growth factor‐responsive phosphorylation of the amino acid‐responsive Rag GTPase exemplifies a new interplay between the two parallel main pathways of mTORC1 regulation. [ABSTRACT FROM AUTHOR]

Published
2019
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47. TrpA1 Regulates Thermal Nociception in Drosophila

Author

Neely, G. Gregory, primary, Keene, Alex C., additional, Duchek, Peter, additional, Chang, Elaine C., additional, Wang, Qiao-Ping, additional, Aksoy, Yagiz Alp, additional, Rosenzweig, Mark, additional, Costigan, Michael, additional, Woolf, Clifford J., additional, Garrity, Paul A., additional, and Penninger, Josef M., additional

Published
2011
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