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MyoD Synergizes with the E-Protein HEBß To Induce Myogenic Differentiation

Maura H. Parker,^1,2, Robert L. S. Perry,^3, Mélanie C. Fauteux,¹ Charlotte A. Berkes,⁴ and Michael A. Rudnicki^1,2,5*

Ottawa Health Research Institute, Molecular Medicine Program, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada,¹ McMaster University, Medical Sciences Program, Hamilton, Ontario, Canada,² McMaster University, Department of Biology, Hamilton, Ontario, Canada,³ Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, Washington,⁴ University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada⁵

Received 17 December 2005/ Returned for modification 8 February 2006/ Accepted 8 May 2006

The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. The E-protein HEB is alternatively spliced to generate and ß isoforms. While the function of these molecules has been studied in other cell types, questions persist regarding the molecular functions of HEB proteins in skeletal muscle. Our data demonstrate that HEB expression remains unchanged in both myoblasts and myotubes, whereas HEBß is upregulated during the early phases of terminal differentiation. Upon induction of differentiation, a MyoD-HEBß complex bound the E1 E-box of the myogenin promoter leading to transcriptional activation. Importantly, forced expression of HEBß with MyoD synergistically lead to precocious myogenin expression in proliferating myoblasts. However, after differentiation, HEB and HEBß synergized with myogenin, but not MyoD, to activate the myogenin promoter. Specific knockdown of HEBß by small interfering RNA in myoblasts blocked differentiation and inhibited induction of myogenin transcription. Therefore, HEB and HEBß play novel and central roles in orchestrating the regulation of myogenic factor activity through myogenic differentiation.

Present address: Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Wash.

Present address: Department of Biology, York University, Toronto, Ontario, Canada.

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