IRF8 regulates B-cell lineage specification, commitment, and differentiation.
PU.1, IKAROS, E2A, EBF, and PAX5 comprise a transcriptional network that orchestrates B-cell lineage specification, commitment, and differentiation. Here we identify interferon regulatory factor 8 (IRF8) as another component of this complex, and show that it also modulates lineage choice by hematopoietic stem cells (HSCs). IRF8 binds directly to an IRF8/Ets consensus sequence located in promoter regions of Sfpi1 and Ebf1, which encode PU.1 and EBF, respectively, and is associated with transcriptional repression of Sfpi1 and transcriptional activation of Ebf1. Bone marrows of IRF8 knockout mice (IRF8(-/-)) had significantly reduced numbers of pre-pro-B cells and increased numbers of myeloid cells. Although HSCs of IRF8(-/-) mice failed to differentiate to B220(+) B-lineage cells in vitro, the defect could be rescued by transfecting HSCs with wild-type but not with a signaling-deficient IRF8 mutant. In contrast, overexpression of IRF8 in HSC-differentiated progenitor cells resulted in growth inhibition and apoptosis. We also found that IRF8 was expressed at higher levels in pre-pro-B cells than more mature B cells in wild-type mice. Together, these results indicate that IRF8 modulates lineage choice by HSCs and is part of the transcriptional network governing B-cell lineage specification, commitment, and differentiation.
Wang
Hongsheng
H
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. wanghongs@niaid.nih.gov
Lee
Chang Hoon
CH
Qi
Chenfeng
C
Tailor
Prafullakumar
P
Feng
Jianxun
J
Abbasi
Sadia
S
Atsumi
Toru
T
Morse
Herbert C
HC
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000378:metabolism*; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
D051792:Basic Helix-Loop-Helix Proteins; D051740:Ikaros Transcription Factor; D050835:Interferon Regulatory Factors; D017493:Leukocyte Common Antigens; D051757:PAX5 Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; C489921:Ebf1 protein, mouse; C497282:Pax5 protein, mouse; C075668:Tcf3 protein, mouse; C497238:Zfpn1a1 protein, mouse
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