Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
- University of Melbourne, Australia
- QIMR Berghofer Medical Research Institute, Australia
- University of California, Irvine, United States
- University of Sydney, Australia
- University of California, Los Angeles, United States
Abstract
Improving muscle function has great potential to improve the quality of life. To identify novel regulators of skeletal muscle metabolism and function, we performed a proteomic analysis of gastrocnemius muscle from 73 genetically distinct inbred mouse strains, and integrated the data with previously acquired genomics and >300 molecular/phenotypic traits via quantitative trait loci mapping and correlation network analysis. These data identified thousands of associations between protein abundance and phenotypes and can be accessed online (https://muscle.coffeeprot.com/) to identify regulators of muscle function. We used this resource to prioritize targets for a functional genomic screen in human bioengineered skeletal muscle. This identified several negative regulators of muscle function including UFC1, an E2 ligase for protein UFMylation. We show UFMylation is up-regulated in a mouse model of amyotrophic lateral sclerosis, a disease that involves muscle atrophy. Furthermore, in vivo knockdown of UFMylation increased contraction force, implicating its role as a negative regulator of skeletal muscle function.
Data availability
The proteomics data generated in this study are deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al., 2019) under the identifiers PXD032729, PXD034913 and PXD035170. The code used for downstream analysis of proteomic data can be found at: https://github.com/JeffreyMolendijk/skeletal_muscle.
Article and author information
Author details
Funding
National Health and Medical Research Council (APP1184363)
- Karen Reue
- Marcus M Seldin
- Benjamin L Parker
National Institute of Health (HL147883)
- Aldons J Lusis
National Institute of Health (DK117850)
- Aldons J Lusis
Weary Dunlop Foundation (NA)
- Benjamin L Parker
The ALS Association (21-DDC-574)
- Paul Gregorevic
- Peter J Crouch
National Health and Medical Research Council (APP2009642)
- Benjamin L Parker
National Health and Medical Research Council (APP2013189)
- Richard J Mills
National Health and Medical Research Council (APP1156562)
- Paul Gregorevic
- Benjamin L Parker
National Institute of Health (HL138193)
- Marcus M Seldin
National Institute of Health (DK130640)
- Marcus M Seldin
National Institute of Health (DK097771)
- Marcus M Seldin
National Institute of Health (GM115318)
- Karen Reue
National Institute of Health (AG070959)
- Aldons J Lusis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Charles Farber, University of Virginia, United States
Ethics
Animal experimentation: All rAAV6 intramuscular injection mouse experiments were approved by The University of Melbourne Animal Ethics Committee (AEC ID1914940) and conformed to the National Health and Medical Research Council of Australia guidelines regarding the care and use of experimental animals. All studies involving the use of SOD1G37R mice and non-transgenic littermates were approved by a University of Melbourne Animal Experimentation Ethics Committee (approval #2015124) and conformed with guidelines of the Australian National Health and Medical Research Council.
Version history
- Preprint posted: August 22, 2022 (view preprint)
- Received: August 24, 2022
- Accepted: November 29, 2022
- Accepted Manuscript published: December 6, 2022 (version 1)
- Version of Record published: January 11, 2023 (version 2)
Copyright
© 2022, Molendijk et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,502
- views
-
- 221
- downloads
-
- 9
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
eLife 11:e82951.
https://doi.org/10.7554/eLife.82951
Further reading
-
- Computational and Systems Biology
- Evolutionary Biology
A comprehensive census of McrBC systems, among the most common forms of prokaryotic Type IV restriction systems, followed by phylogenetic analysis, reveals their enormous abundance in diverse prokaryotes and a plethora of genomic associations. We focus on a previously uncharacterized branch, which we denote coiled-coil nuclease tandems (CoCoNuTs) for their salient features: the presence of extensive coiled-coil structures and tandem nucleases. The CoCoNuTs alone show extraordinary variety, with three distinct types and multiple subtypes. All CoCoNuTs contain domains predicted to interact with translation system components, such as OB-folds resembling the SmpB protein that binds bacterial transfer-messenger RNA (tmRNA), YTH-like domains that might recognize methylated tmRNA, tRNA, or rRNA, and RNA-binding Hsp70 chaperone homologs, along with RNases, such as HEPN domains, all suggesting that the CoCoNuTs target RNA. Many CoCoNuTs might additionally target DNA, via McrC nuclease homologs. Additional restriction systems, such as Type I RM, BREX, and Druantia Type III, are frequently encoded in the same predicted superoperons. In many of these superoperons, CoCoNuTs are likely regulated by cyclic nucleotides, possibly, RNA fragments with cyclic termini, that bind associated CARF (CRISPR-Associated Rossmann Fold) domains. We hypothesize that the CoCoNuTs, together with the ancillary restriction factors, employ an echeloned defense strategy analogous to that of Type III CRISPR-Cas systems, in which an immune response eliminating virus DNA and/or RNA is launched first, but then, if it fails, an abortive infection response leading to PCD/dormancy via host RNA cleavage takes over.
-
- Computational and Systems Biology
Imputing data is a critical issue for machine learning practitioners, including in the life sciences domain, where missing clinical data is a typical situation and the reliability of the imputation is of great importance. Currently, there is no canonical approach for imputation of clinical data and widely used algorithms introduce variance in the downstream classification. Here we propose novel imputation methods based on determinantal point processes (DPP) that enhance popular techniques such as the multivariate imputation by chained equations and MissForest. Their advantages are twofold: improving the quality of the imputed data demonstrated by increased accuracy of the downstream classification and providing deterministic and reliable imputations that remove the variance from the classification results. We experimentally demonstrate the advantages of our methods by performing extensive imputations on synthetic and real clinical data. We also perform quantum hardware experiments by applying the quantum circuits for DPP sampling since such quantum algorithms provide a computational advantage with respect to classical ones. We demonstrate competitive results with up to 10 qubits for small-scale imputation tasks on a state-of-the-art IBM quantum processor. Our classical and quantum methods improve the effectiveness and robustness of clinical data prediction modeling by providing better and more reliable data imputations. These improvements can add significant value in settings demanding high precision, such as in pharmaceutical drug trials where our approach can provide higher confidence in the predictions made.
