Carbon metabolism–mediated myogenic differentiation

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Abstract

The role of nutrients and metabolism in cellular differentiation is poorly understood. Using RNAi screening, metabolic profiling and small-molecule probes, we discovered that the knockdown of three metabolic enzymes—phosphoglycerate kinase (Pgk1), hexose-6-phosphate dehydrogenase (H6pd) and ATP citrate lyase (Acl)—induces differentiation of mouse C2C12 myoblasts even in the presence of mitogens. These enzymes and the pathways they regulate provide new targets for the control of myogenic differentiation in myoblasts and rhabdomyosarcoma cells.

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Figure 1: RNAi screen and effects of CsA and TSA on C2C12 differentiation.
Figure 2: Fluvastatin treatment causes differentiation of human rhabdomyosarcoma cells and inhibits their proliferation and growth on soft agar.

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Acknowledgements

We thank the RNAi Consortium for shRNAs and the following members of the RNAi platform of the Broad Institute for their scientific advising: A. Derr, J. Grenier, S. Silver, G. Cowley and O. Alkan. We also thank S. Carr, R. Wei, E. Yang and members of the Broad Institute metabolic profiling platform for scientific advice and analysis of metabolite extracts, and J. Nisbet of Children's Hospital Boston for thoughtful comments. This work was supported in part by US Department of Defense Breast Cancer Innovator Award #BC074986 (to D.E.I.) and US National Institute of General Medical Sciences grant 38627 (to S.L.S.). S.L.S. is an investigator with the Howard Hughes Medical Institute. A.L.B. was supported in part by the US National Science Foundation.

Author information

A.L.B. designed and performed the RNAi screen, all validation experiments, quantitative RT-PCR, generation of stable cell lines and studies on cyclosporin, cholesterol and trichostatin. A.R. designed and performed metabolite experiments and the histone acetylation study. S.L.S. participated in the design of the overall study. S.H., D.E.I. and S.L.S. contributed to the preparation of the manuscript. D.E.I. and A.L.B. conceived of the idea for this study. All authors interpreted data, commented on results and participated in writing the manuscript.

Correspondence to Arvind Ramanathan or Stuart L Schreiber.

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Supplementary Figures 1-3, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 780 kb)

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