Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation.
Skeletal muscle development is controlled by the myocyte enhancer factor (MEF2) and myogenic basic helix-loop-helix (bHLH) families of transcription factors, which associate and synergistically activate muscle gene expression. Muscle differentiation is further reinforced by positive-feedback loops in which myogenic bHLH proteins activate their own expression and the expression of MEF2, while MEF2 stimulates expression of myogenic bHLH genes and the Mef2c gene. Here we describe a myogenic negative-feedback loop that consists of MEF2 proteins and the transcriptional repressor histone deacetylase 9 (HDAC9). We show that the HDAC9 gene is a direct transcriptional target of MEF2 in vitro and in vivo. HDAC9 can associate with MEF2 proteins and suppress their transcriptional activity. The transcriptional repressor HDAC9 thus forms a negative-feedback loop in the transcriptional circuitry of muscle differentiation.
Haberland
Michael
M
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Arnold
Michael A
MA
McAnally
John
J
Phan
Dillon
D
Kim
Yuri
Y
Olson
Eric N
EN
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; C578041:Mef2c protein, mouse; C578044:Mef2d protein, mouse; C486545:Hdac9 protein, mouse