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J. Biol. Chem., Vol. 277, Issue 41, 38390-38398, October 11, 2002

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Genomic Structures of the Human and Murine Corin Genes and Functional GATA Elements in Their Promoters^*

Junliang Pan^§, Bernd Hinzmann^¶, Wei Yan, Faye Wu, John Morser, and Qingyu Wu

From the  Department of Cardiovascular Research, Berlex Biosciences, Richmond, California 94806 and ^¶ metaGen Pharmaceuticals, Berlin 13347, Germany

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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF521006.

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