HNF-1beta regulates transcription of the PKD modifier gene Kif12.
Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor that regulates gene expression in the kidney, liver, pancreas, and other epithelial organs. Mutations of HNF-1beta lead to a syndrome of inherited renal cysts and diabetes and are also a common cause of sporadic renal dysplasia. The full complement of target genes responsible for the functions of HNF-1beta, however, is incompletely defined. Using a functional genomics approach involving chromatin immunoprecipitation and promoter arrays, combined with gene expression profiling, we found that an HNF-1beta target gene in the kidney is kinesin family member 12 (Kif12), a gene previously identified as a candidate modifier gene in the cpk mouse model of polycystic kidney disease. Mutations of HNF-1beta inhibited Kif12 transcription in both cultured cells and knockout mice by altering co-factor recruitment and histone modification. Because kinesin-12 family members participate in orienting cell division, downregulation of Kif12 may underlie the abnormal planar cell polarity observed in cystic kidney diseases.
Gong
Yimei
Y
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ma
Zhendong
Z
Patel
Vishal
V
Fischer
Evelyne
E
Hiesberger
Thomas
T
Pontoglio
Marco
M
Igarashi
Peter
P
D000818:Animals; D050882:CREB-Binding Protein / Q000502:physiology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D051539:Hepatocyte Nuclear Factor 1-beta / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D016547:Kinesins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
C503459:KIF12 protein, mouse; D051539:Hepatocyte Nuclear Factor 1-beta; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D016547:Kinesins