Molecular Mechanisms Underlying Heme Regulation Of Exocrine Peptidase Precursor Genes In Zebrafish

In addition to being the prosthetic group for numerous proteins such as hemoglobin,catalases, and cytochromes, heme also as a signaling molecule modulates a number ofmolecular and cellular processes. Defects in the enzymes involved in the hemebiosynthetic pathway result in a group of human diseases known as porphyrias oranemia. Previously, we established a UROD-deficient zebrafish yqetp61as a model forstudying human hepatoerythropoietic porphyria (HEP) and porphyria cutanea tarda(PCT), and reported downregulation of six exocrine peptidase precursor genes,carboxypeptidase A (cpa), trypsin precursor (try),trypsin like (tryl), chymotrypsinogenB1(ctrb1), chymotrypsinogen1like (ctr1l), and elastase2like (ela2l), in yquem/urod(-/-). However, molecular genetic mechanisms underlying heme regulation of theseexocrine peptidase precursor genes are still unknown. Here we show thatoverexpression of bach1and knockdown of nrf2all result in downregulation of theseexocrine peptidase precursor genes in zebrafish, whereas overexpression of nrf2andknockdown of bach1all result in upregulation of these exocrine peptidase precursorgenes in zebrafish. MafK protein can recognize and bind the Maf recognition element(MARE) in the regulatory regions of these exocrine peptidase precursor genes. MafKserves as dual-function transcription factors through an exchange of itsheterodimerization partner. When heterodimerized with MafK, Nrf2activates theseexocrine peptidase precursor genes, whilst Bach1represses these same genes whenheterodimerized with MafK. These findings provide novel insights into heme deficiencypathogenesis, and new approaches to diagnosing and treatment of patients withporphyria or pancreatic diseases.