HRC is a direct transcriptional target of MEF2 during cardiac, skeletal, and arterial smooth muscle development in vivo.
The HRC gene encodes the histidine-rich calcium-binding protein, which is found in the lumen of the junctional sarcoplasmic reticulum (SR) of cardiac and skeletal muscle and within calciosomes of arterial smooth muscle. The expression of HRC in cardiac, skeletal, and smooth muscle raises the possibility of a common transcriptional mechanism governing its expression in all three muscle cell types. In this study, we identified a transcriptional enhancer from the HRC gene that is sufficient to direct the expression of lacZ in the expression pattern of endogenous HRC in transgenic mice. The HRC enhancer contains a small, highly conserved sequence that is required for expression in all three muscle lineages. Within this conserved region is a consensus site for myocyte enhancer factor 2 (MEF2) proteins that we show is bound efficiently by MEF2 and is required for transgene expression in all three muscle lineages in vivo. Furthermore, the entire HRC enhancer sequence lacks any discernible CArG motifs, the binding site for serum response factor (SRF), and we show that the enhancer is not activated by SRF. Thus, these studies identify the HRC enhancer as the first MEF2-dependent, CArG-independent transcriptional target in smooth muscle and represent the first analysis of the transcriptional regulation of an SR gene in vivo.
Anderson
Joshua P
JP
Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130, USA.
Dodou
Evdokia
E
Heidt
Analeah B
AB
De Val
Sarah J
SJ
Jaehnig
Eric J
EJ
Greene
Stephanie B
SB
Olson
Eric N
EN
Black
Brian L
BL
D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006321:Heart / Q000196:embryology* / Q000502:physiology; D006801:Humans; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000196:embryology* / Q000502:physiology; D018006:Myogenic Regulatory Factors; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C489418:Hrc protein, mouse; D064326:MEF2 Transcription Factors; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; C068969:HRC protein, human