Regulation of delta-aminolevulinic acid dehydratase by krüppel-like factor 1.
Krüppel-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 β-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 eviction at the Alad1b promoter. Furthermore, KLF1-dependent events were not modulated by GATA1 factor promoter co-occupancy alone. These results not only enhance our understanding of erythroid-specific modulation of heme biosynthetic regulation by KLF1, but provide a model that will facilitate the elucidation of novel KLF1-dependent events at erythroid gene loci that are independent of GATA1 activity.
Section of Hematology/Oncology and Stem Cell Transplantation, Department of Pediatrics, University of Chicago, Chicago, Illinois, USA. adesgard@gmail.com
Aurelie D
AD
Desgardin
Tatiana
T
Abramova
Tolulope O
TO
Rosanwo
Sreedharan
S
Kartha
Eun-Hee
EH
Shim
Stephen M
SM
Jane
John M
JM
Cunningham
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006657:Histones / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D000623:Porphobilinogen Synthase / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
D017931:DNA Primers; D006657:Histones; D051741:Kruppel-Like Transcription Factors; C080774:erythroid Kruppel-like factor; D013629:Tamoxifen; C016601:afimoxifene; D012319:RNA Polymerase II; D000623:Porphobilinogen Synthase