Myeloid expression of cytochrome P450 4F3 is determined by a lineage-specific alternative promoter.
The cytochrome P450 4F3 (CYP4F3) gene encodes two functionally distinct enzymes that differ only by the selection of exon 4 (CYP4F3A) or exon 3 (CYP4F3B). CYP4F3A inactivates leukotriene B4, a reaction that has significance for controlling inflammation. CYP4F3B converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a potent activator of protein kinase C. We have previously shown that mRNAs coding for CYP4F3A and CYP4F3B are generated from distinct transcription start sites in neutrophils and liver. We therefore investigated mechanisms that regulate the cell-specific expression of these two isoforms. Initially, we analyzed the distribution of CYP4F3 in human leukocytes and determined a lineage-specific pattern of isoform expression. CYP4F3A is expressed in myeloid cells and is coordinate with myeloid differentiation markers such as CD11b and myeloperoxidase during development in the bone marrow. In contrast, CYP4F3B expression is restricted to a small population of CD3+ T lymphocytes. We identified distinct transcriptional features in myeloid, lymphoid, and hepatic cells that indicate the presence of multiple promoters in the CYP4F3 gene. The hepatic promoter depends on a cluster of hepatocyte nuclear factor sites 123-155 bp upstream of the initiator ATG codon. The myeloid promoter spans 400 bp in a region 468-872 bp upstream of the ATG codon; it is associated with clusters of CACCT sites and can be activated by ZEB-2, a factor primarily characterized as a transcriptional repressor in cells that include lymphocytes. ZEB-2 interacts with C-terminal binding protein and Smads, and this would provide opportunities for integrating environmental signals in myelopoiesis and inflammation.
Christmas
Peter
P
Renal Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129, USA. christma@helix.mgh.harvard.edu
Carlesso
Nadia
N
Shang
Haibo
H
Cheng
Shing-Ming
SM
Weber
Brittany M
BM
Preffer
Frederic I
FI
Scadden
David T
DT
Soberman
Roy J
RJ
D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology*; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C465349:CYP4F3 protein, human