Genomic structures of the human and murine corin genes and functional GATA elements in their promoters.
Corin is a multiple-domain type II transmembrane serine protease highly expressed in the heart. It converts pro-atrial natriuretic peptide to atrial natriuretic peptide, a cardiac hormone that regulates blood volume and pressure. Here we describe the genomic structures of the human and murine corin genes and functional analysis of their promoters. Both corin genes contain 22 exons and span >200 kb. Their intron/exon boundaries are well conserved, with most exons encoding distinct structural domains, supporting the idea that corin evolved as a result of exon duplication and rearrangement. Comparison of the 5'-flanking regions of the human and murine corin genes revealed several conserved sequences, including binding sites for TBX5, GATA, NKX2.5, and Krüppel-like transcription factors. Transfection experiments with reporter gene constructs driven by the human or murine corin 5'-flanking region indicated that the sequences from -405 to -15 in human and from -646 to -77 in mouse are sufficient to promote high levels of gene expression in murine cardiomyocytes. In contrast, these sequences produced only minimal levels of expression in HeLa cells. Within these sequences, we identified a conserved GATA element that bound to GATA-4. Mutation of the core sequence impaired both GATA-4 binding and gene expression. These data indicate that the GATA element and its binding to GATA-4 are essential for cardiac expression of the human and murine corin genes.
Pan
Junliang
J
Department of Cardiovascular Research, Berlex Biosciences, Richmond, California 94806, USA. junliang_pan@berlex.com
Hinzmann
Bernd
B
Yan
Wei
W
Wu
Faye
F
Morser
John
J
Wu
Qingyu
Q
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics; D050991:GATA4 Transcription Factor; D005786:Gene Expression Regulation; D005796:Genes; D017930:Genes, Reporter; D006367:HeLa Cells; D006321:Heart / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D008565:Membrane Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C119812:CORIN protein, human; C485617:Corin protein, mouse; D012697:Serine Endopeptidases