Authors: Aurora Hernández Ana Villegas Eduardo Anguita
Publish Date: 2010/02/09
Volume: 89, Issue: 8, Pages: 759-765
Abstract
Growth factorindependence 1b Gfi1b is a zinc finger transcription factor essential for erythroid and megakaryocytic development To better understand Gfi1b regulation and to know the implication of the level of expression of this gene in human pathology we have searched for promoter punctual sequence variations in 214 patients with different hematological diseases We found two previously unknown congenital mutations at evolutionary conserved GATA and octamerbinding Oct transcription factor sites The Oct site mutation was also found in five relatives of the patient The GATA motif mutation reduced promoter activity by 50 in vitro while homozygous patients with the octamer site mutation showed a fourtofive times increase of Gfi1b RNA in platelets Electrophoretic mobility shift analyses demonstrated that different protein complexes bind to both sites and that binding is reduced by the mutations Finally we found that GATA1 and Oct1 are the main components of each complex This study provides evidences of a new mechanism for Gfi1b repression This is also the first report of Gfi1b mutations with a functional implication further investigation and followup will clarify the involvement of these mutations in hematological diseaseThe authors would like to thank William G Wood for the advice animal samples and support and Christopher Fisher for technical help both in Weatherall Institute of Molecular Medicine Oxford University We also thank Angel Remacha Virgen de la Salud Hospital Toledo Spain for patient samples and the Epidemiology Department at Hospital Clinico San Carlos for their help with the statistical analysis
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