Identification of target genes of the transcription factor HNF1 beta and HNF1 alpha in a human embryonic kidney cell line

摘要

Hepatocyte nuclear factor I beta (HNF1 beta, TCF2) is a tissue-specific transcription factor whose Mutation in humans leads to renal cysts, genital malfon-nations, pancreas atrophy and maturity onset diabetes of the Young (MODY5). Furthermore, HNF1 beta overexpression has been observed in clear cell cancer of the ovary. To identify potential HNF1 beta target genes whose activity may be deregulated in human patients, we established a human embryonic kidney cell line (HEK293) expressing HNF I conditionally. Using Fill recornbinase, we introduced wild type or mutated HNF1 beta at a defined chromosomal position allowing a most reproducible induction of the HNF1 beta derivatives upon tetracycline addition. By oligonucleotide microarrays we identified 25 HNF1 beta-regulatecl genes. By ail identical approach, we identified that the related transcription factor HNF1 alpha (TCF1) affects only nine genes in HEK293 cells and thus is a less efficient factor in these kidney cells. The HNF1 beta target genes dipeptidyl pepticiase 4 (DPP4), angiotensin converting enzyme 2 (ACE2) and osteopontin (SPP1) are most likely direct target genes, as they contain functional HNF1 binding sites in their promoter region. Since nine of the potential HNF1 beta target genes are deregulated in clear cell carcinoma of the ovary, we propose that HNF1 beta overexpression in the ovarian cancer participates in the altered expression pattern. (c) 2005 Elsevier B.V. All rights reserved.