regulation of delta-aminolevulinic acid dehydratase by krüppel-like factor 1监管kruppel-like delta-aminolevulinic酸脱水酶的因素1.pdfVIP

Regulation of Delta-Aminolevulinic Acid Dehydratase by ¨ Kruppel-Like Factor 1 1 1 1 1 1 Aurelie D. Desgardin *, Tatiana Abramova , Tolulope O. Rosanwo , Sreedharan Kartha , Eun-Hee Shim , Stephen M. Jane3, John M. Cunningham1,2 1 Section of Hematology/Oncology and Stem Cell Transplantation, Department of Pediatrics, University of Chicago, Chicago, Illinois, United States of America, 2 Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, Illinois, United States of America, 3 Australian Centre for Blood Diseases, Monash University Department of Clinical Hematology, Alfred Hospital, Melbourne, Australia Abstract ¨ Kruppel-like factor 1(KLF1) is a hematopoietic-specific zinc finger transcription factor essential for erythroid gene expression. In concert with the transacting factor GATA1, KLF1 modulates the coordinate expression of the genes encoding the multi- enzyme heme biosynthetic pathway during erythroid differentiation. To explore the mechanisms underpinning KLF1 action at the gene loci regulating the first 3 steps in this process, we have exploited the K1-ERp erythroid cell line, in which KLF1 translocates rapidly to the nucleus in response to treatment with 4-OH-Tamoxifen (4-OHT). KLF1 acts as a differentiation- independent transcriptional co-regulator of delta-aminolevulinic acid dehydratase (Alad), but not 5-aminolevulinate synthase gene (Alas2) or porphobilinogen deaminase (Pbgd). Similar to its role at the b-globin promoter, KLF1 induces factor recruitment and chromatin changes at the Alad1b promoter in a temporally-specific manner. In contrast to these changes, we observed a distinct mechanism of histone ev