Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros.
The transcription factor Ikaros is essential for B cell development. However, its molecular functions in B cell fate specification and commitment have remained elusive. We show here that the transcription factor EBF restored the generation of CD19(+) pro-B cells from Ikaros-deficient hematopoietic progenitors. Notably, these pro-B cells, despite having normal expression of the transcription factors EBF and Pax5, were not committed to the B cell fate. They also failed to recombine variable gene segments at the immunoglobulin heavy-chain locus. Ikaros promoted heavy-chain gene rearrangements by inducing expression of the recombination-activating genes as well as by controlling accessibility of the variable gene segments and compaction of the immunoglobulin heavy-chain locus. Thus, Ikaros is an obligate component of a network that regulates B cell fate commitment and immunoglobulin heavy-chain gene recombination.
Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois 60637, USA.
Damien
D
Reynaud
Ignacio A
IA
Demarco
Karen L
KL
Reddy
Hilde
H
Schjerven
Eric
E
Bertolino
Zhengshan
Z
Chen
Stephen T
ST
Smale
Susan
S
Winandy
Harinder
H
Singh
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001665:Binding Sites; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D015321:Gene Rearrangement / Q000235:genetics / Q000276:immunology; D005803:Genes, Immunoglobulin / Q000235:genetics*; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D045567:VDJ Recombinases / Q000235:genetics*
D007143:Immunoglobulin Heavy Chains; D051740:Ikaros Transcription Factor; D045567:VDJ Recombinases