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Science 329 (5996): 1201-1205

Copyright © 2010 by the American Association for the Advancement of Science

Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation

David Bungard,1 Benjamin J. Fuerth,2,3 Ping-Yao Zeng,1,4 Brandon Faubert,2,3 Nancy L. Maas,1 Benoit Viollet,5,6 David Carling,7 Craig B. Thompson,8 Russell G. Jones,2,3,8,* Shelley L. Berger1,9,10,*

Abstract: The mammalian adenosine monophosphate–activated protein kinase (AMPK) is a serine-threonine kinase protein complex that is a central regulator of cellular energy homeostasis. However, the mechanisms by which AMPK mediates cellular responses to metabolic stress remain unclear. We found that AMPK activates transcription through direct association with chromatin and phosphorylation of histone H2B at serine 36. AMPK recruitment and H2B Ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions. Ectopic expression of H2B in which Ser36 was substituted by alanine reduced transcription and RNA polymerase II association to AMPK-dependent genes, and lowered cell survival in response to stress. Our results place AMPK-dependent H2B Ser36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.

1 Department of Cellular and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
2 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada.
3 Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
4 Institutes of Biomedical Sciences Epigenetics Program, Mingdao Building, Room 511, Fudan University, Mail Box 281, 138 Yixue Yuan Road, Shanghai 200032, P.R. China.
5 Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France.
6 INSERM U1016, 75014 Paris, France.
7 Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London W12 0NN, UK.
8 Abramson Cancer Center and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
9 Department of Genetics, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
10 Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: russell.jones{at} (R.G.J.); bergers{at} (S.L.B.)

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