A recurrent network involving the transcription factors PU.1 and Gfi1 orchestrates innate and adaptive immune cell fates.
The transcription factor PU.1, encoded by the Sfpi1 gene, functions in a graded manner to regulate macrophage versus B cell generation; its higher concentration favors the macrophage fate. We demonstrated that Gfi1 reciprocally promoted B cell fate choice at the expense of myeloid progeny. Gfi1(-/-) multipotential progenitors (MPPs) were unable to constrain the expression of PU.1 because Gfi1 functioned to repress the Sfpi1 gene by displacing PU.1 from positive autoregulatory elements. Attenuating a transcriptional module composed of PU.1 and Egr suppressed the B lineage developmental defects of Gfi1(-/-) MPPs. Finally Ikaros, a transcription factor required for B cell development, promoted Gfi1 and antagonized PU.1 expression in MPPs. Our results reveal that a core transcriptional regulatory network used for directing cell fate choice in the innate immune system has been co-opted by Ikaros to orchestrate B lymphocyte generation. These findings have important implications for the evolution of the adaptive immune system.
Spooner
Chauncey J
CJ
Howard Hughes Medical Institute, The University of Chicago, GCIS W522, Chicago, IL 60637, USA.
Cheng
Jason X
JX
Pujadas
Elisabet
E
Laslo
Peter
P
Singh
Harinder
H
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053263:Gene Regulatory Networks / Q000276:immunology; D051740:Ikaros Transcription Factor / Q000276:immunology / Q000378:metabolism*; D007110:Immunity, Active; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D004268:DNA-Binding Proteins; D051740:Ikaros Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C079873:Gfi1 protein, mouse; C497238:Zfpn1a1 protein, mouse