MyoD synergizes with the E-protein HEB beta to induce myogenic differentiation.
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 alpha and beta 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 alpha expression remains unchanged in both myoblasts and myotubes, whereas HEB beta is upregulated during the early phases of terminal differentiation. Upon induction of differentiation, a MyoD-HEB beta complex bound the E1 E-box of the myogenin promoter leading to transcriptional activation. Importantly, forced expression of HEB beta with MyoD synergistically lead to precocious myogenin expression in proliferating myoblasts. However, after differentiation, HEB alpha and HEB beta synergized with myogenin, but not MyoD, to activate the myogenin promoter. Specific knockdown of HEB beta by small interfering RNA in myoblasts blocked differentiation and inhibited induction of myogenin transcription. Therefore, HEB alpha and HEB beta play novel and central roles in orchestrating the regulation of myogenic factor activity through myogenic differentiation.
Parker
Maura H
MH
Ottawa Health Research Institute, Molecular Medicine Program, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.
Perry
Robert L S
RL
Fauteux
Mélanie C
MC
Berkes
Charlotte A
CA
Rudnicki
Michael A
MA
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000502:physiology*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D048369:MAP Kinase Kinase 1; D017570:MyoD Protein; D018008:Myogenin; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C489532:Tcf12 protein, mouse