5 May 2019
Protein phosphorylation is a major regulator of transcriptional and/or epigenetic control during early embryogenesis. Yet the timing, extent and composition of molecular events, including phosphorylation, that underpin the developmental transformation of pre-implantation epiblast to post-implantation epiblast remain poorly understood. In collaboration with the National Institutes of Health and the Max Planck Institute of Biochemistry we have performed extensive mapping of global changes to the proteome, phosphoproteome, transcriptome, and epigenome of embryonic stem cells transitioning from naïve to primed pluripotency, uncovering a complex and multi-layered network controlling pluripotency progression.
Yang P*, Humphrey SJ*, Cinghu S*,… James DE, Mann M and Jothi R. Multi-Omic Profiling Reveals Dynamics of the Phased Progression of Pluripotency. Cell Systems 8, 1-19, (2019).
28 February 2019
Early signs of fatty liver disease detected in blood
Accumulation of fat in the liver, known as fatty liver disease, is experienced by over 5.5 million Australians, including more than 40 percent of all adults over the age of 50.
Fatty liver develops from a combination of both genetic and environmental causes, which influence the age of onset and severity of the disease. Experts are now describing the condition as a hidden epidemic, which is driving up rates of liver transplant, contributing to a range of illnesses and ultimately death.
Fatty liver disease usually has no early symptoms and diagnoses with current technologies mostly comes too late to prevent major illness.
But now, for the first time in a study published in the prestigious scientific journal, Nature, a team of researchers from the Baker Heart and Diabetes Institute, University of California and University of Sydney, have discovered biomarkers in the blood that can predict the accumulation of toxic fats in the liver, which are a sign of early fatty liver disease. These predictions can be made based on the lipid (fats) profile in the blood.
Dr Benjamin Parker, who was an NHMRC Research Fellow at the Charles Perkins Centre and the School of Life and Environmental Sciences at the University of Sydney and drove the project, said the study aimed to understand the underlying mechanisms of metabolic diseases such as diabetes.
“Some individuals are more susceptible than others and we don't completely understand why,” Dr Parker said.
“Our study used a new approach to link mutations in DNA to changes in fat metabolism. We have identified several new drug targets and biomarkers to treat or monitor fatty liver disease which is strongly associated with diabetes."
Professor David James from the University of Sydney’s Charles Perkins Centre described the study as a technological tour de force that represented one of the most futuristic approaches for examining complex diseases like diabetes and cardiovascular disease.
“We have simultaneously measured many different layers of the biological system including lipids and other metabolites as well as thousands of proteins and integrated this with genetic information,” he said.
“This has given us an exciting view of how complex diseases like fatty liver occur. Most importantly this approach represents a new way forward in precision medicine, an approach which will transform health care.
The team is now hoping to establish why some people are more prone to fatty liver disease than others.
A big Congratulations to Elise Needhm and Sean Humphrey along with Tim Burykin from the Life Lab for their review article that was published in Science Signaling. Their paper was accompanied by the Front Cover and a Focus article by the Editor Mike Yaffe from Harvard.
The article describes why Cancer research and research into other complex diseases must shift more toward biochemistry and analysis of signal transduction as this represents the disease coal face.
Farewell to two of our lab members - Dr Benjamin Parker and Dr Tim Su!
Ben will be heading to the University of Melbourne where he has been appointed as a group leader. Tim has been appointed as the Assistant Director at ChemPartner Co in Shanghai.
We wish them both all the best for the future. They will be missed around the lab
We would like to welcome both Dr Alexis Diaz and Dr Soren Madsen who have both joined the James Lab as a Postdoctoral Research Associates.
Alexis obtained his Ph.D. in Biomedical Science working with Dr. Enrique Jaimovich in the Muscle Physiology Lab, Faculty of Medicine, University of Chile. During this time, Alexis learnt about the adult skeletal muscle physiology and its metabolic alteration in diet-induced insulin resistance.
In 2018 Alexis won a research fellow to work in mitochondrial metabolism in neonatal cardiomyocyte with Dr. Sergio Lavandero, in the Advanced Center of Chronic Diseases, University of Chile. He was also the national head of the human physiology undergraduate course to Medical Doctor, School of Medicine, University Andrés Bello, Chile.
Soren completed his PhD in 2018 at the University of Copenhagen with Sara Vienberg and Jonas Treebak at CBMR Integrative Physiology. During Soren’s PhD research he studied adipose tissue biology in relation to metabolic stress, such as high-fat diet and exercise. More specifically he was interested in how miRNA matures during times of low or high energy states, as it has become apparent that miRNAs are dysregulated in metabolic disease.
Soren’s current project investigates how genes and environment affect the progression of insulin resistance. Soren’s main focus is on adipose tissue and trying to identify genetic drives that impair glucose uptake into fat.
It is great to have you both on board!
Big Congratulations to all of the following lab members who have achieved some special things recently.
What a great way to wrap up 2018!!
Dr Benjamin Parker has been appointed as a group leader at the University of Melbourne starting in 2019
Dr Daniel Fazakerley has been appointed as a group leader at Cambridge University starting in May 2019
Our PhD student Elise Needham won the best student oral presentation of the year at the Charles Perkins Centre Biology Domain Seminar Series.
Sean Humphrey and his wife are expecting a little baby in January. Go Sean!
James Krycer won the Skip Martin fellowship for 2019.
Daniel Fazakerely received a DART grant.
Well done to Guang Yang on his EMBO J paper on RagC phosphorylation
Membrane Topology of Trafficking Regulator of GLUT4 1 (TRARG1).
Duan et al. describe the membrane topology of trafficking regulator of GLUT1 (TRARG1; formally known as TUSC5). We previously identified TRARG1 as a regulator of GLUT4 trafficking in 2015 (click here)
Duan X, Krycer JR, Cooke KC, Yang G, James DE, Fazakerley DJ.
Muscle and adipose tissue insulin resistance: malady without mechanism?
Fazakerley, Krycer et al. review mechanisms of muscle and adipose insulin resistance.
Fazakerley DJ, Krycer JR, Kearney AL, Hocking SL, James DE.
Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation.
Our collaboration with Mike Murphy (University of Cambridge) and Richard Hartley (University of Glasgow) using a novel compound to show that mitochondrial oxidative stress rapidly induces insulin resistance independently of changes in mitochondrial respiration.
Fazakerley DJ, Minard AY, Krycer JR, Thomas KC, Stöckli J, Harney DJ, Burchfield JG, Maghzal GJ, Caldwell ST, Hartley RC, Stocker R, Murphy MP, James DE.
Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance.
Fazakerley et al. identify that loss of mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance.
See featured on 7News - Click here
See featured in the eLife podcast - Click here
Fazakerley DJ, Chaudhuri R, Yang P, Maghzal GJ, Thomas KC, Krycer JR, Humphrey SJ, Parker BL, Fisher-Wellman KH, Meoli CC, Hoffman NJ, Diskin C, Burchfield JG, Cowley MJ, Kaplan W, Modrusan Z, Kolumam G, Yang JY, Chen DL, Samocha-Bonet D, Greenfield JR, Hoehn KL, Stocker R, James DE.
A gas trapping method for high-throughput metabolic experiments
Krycer et al. developed a novel gas-trapping method for high-throughput metabolic experiments. Adapted for cells grown in 12- or 24-well plates, this can be used to measure substrate oxidation by collecting CO2 or hydrogen sulphide production from cysteine metabolism.
Krycer JR, Diskin C, Nelson ME, Zeng XY, Fazakerley DJ, James DE
The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes
It is well-established that reactive oxygen species (ROS) are linked to insulin resistance. Chaudhuri, Krycer et al. found that although ROS induces substantial changes across the transcriptional landscape in adipocytes, this transcriptional response is not required for ROS to cause insulin resistance. This suggests that ROS acts via other ‘omes, such as post-translational modifications, to cause insulin resistance in adipocytes.
Chaudhuri R, Krycer JR, Fazakerley DJ, Fisher-Wellman KH, Su Z, Hoehn KL, Yang JYH, Kuncic Z, Vafaee F, James DE.
Dynamic Metabolomics Reveals that Insulin Primes the Adipocyte for Glucose Metabolism
Krycer et al. explored how insulin regulates adipocyte metabolism. It is widely-held that energy storage (anabolism) occurs as a substrate accumulates. However, using dynamic tracer metabolomics and overlaying phosphoproteomics data, they found insulin signalling triggers anabolism before substrates accumulated, creating a ‘demand-driven’ system to prime adipocytes for glucose metabolism.
Krycer JR, Yugi K, Hirayama A, Fazakerley DJ, Quek LE, Scalzo R, Ohno S, Hodson MP, Ikeda S, Shoji F, Suzuki K, Domanova W, Parker BL, Nelson ME, Humphrey SJ, Turner N, Hoehn KL, Cooney GJ, Soga T, Kuroda S, James DE
Editor's pick at JBC!
Metabolomic analysis of insulin resistance across different mouse strains and diets
"Insulin resistance is a complex condition with many genetic and environmental determinants. Stöckli et al carried out a comprehensive metabolomic analysis of three different mouse strains on high-fat or standard diets. The analysis showed that, despite individual, environmental, and genetic variation, a combination of three metabolites (C22:1-CoA, C2-carnitine, and C16-ceramide) together formed an accurate signature for predicting insulin resistance."
Jacqueline Stöckli, Kelsey H. Fisher-Wellman, Rima Chaudhuri, Xiao-Yi Zeng, Daniel J. Fazakerley, Christopher C. Meoli, Kristen C. Thomas, Nolan J. Hoffman, Salvatore P. Mangiafico, Chrysovalantou E. Xirouchaki, Chieh-Hsin Yang, Olga Ilkayeva, Kari Wong, Gregory J. Cooney, Sofianos Andrikopoulos, Deborah M. Muoio, and David E. James
Multiplexed Temporal Quantification of the Exercise-regulated Plasma Peptidome
The latest paper by Parker et al. has been one the most highly viewed article of the Journal of Molecular & Cellular Proteomics during the past month!
Benjamin L. Parker, James G. Burchfield, Daniel Clayton, Thomas A. Geddes, Richard J. Payne, Bente Kiens, Jørgen F. P. Wojtaszewski, Erik A. Richter and David E. James