Affiliation:
1. Max Planck Institute of Immunobiology, Department of Cellular and Molecular Immunology, 79108 Freiburg, Germany
2. MRC Clinical Science Centre, Hammersmith Hospital, London W12 ONN, United Kingdom
3. Institute of Molecular Pathology, Vienna, Austria
Abstract
ABSTRACT
Early differentiation of B lymphocytes requires the function of multiple transcription factors that regulate the specification and commitment of the lineage. Loss- and gain-of-function experiments have provided important insight into the transcriptional control of B lymphopoiesis, whereby E2A was suggested to act upstream of EBF1 and Pax5 downstream of EBF1. However, this simple hierarchy cannot account for all observations, and our understanding of a presumed regulatory network, in which transcription factors and signaling pathways operate, is limited. Here, we show that the expression of the
Ebf1
gene involves two promoters that are differentially regulated and generate distinct protein isoforms. We find that interleukin-7 signaling, E2A, and EBF1 activate the distal
Ebf1
promoter, whereas Pax5, together with Ets1 and Pu.1, regulates the stronger proximal promoter. In the absence of Pax5, the function of the proximal
Ebf1
promoter and accumulation of EBF1 protein are impaired and the replication timing and subcellular localization of the
Ebf1
locus are altered. Taken together, these data suggest that the regulation of
Ebf1
via distinct promoters allows for the generation of several feedback loops and the coordination of multiple determinants of B lymphopoiesis in a regulatory network.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
143 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献