Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros

Damien Reynaud; Ignacio A. Demarco; Karen L. Reddy; Hilde Schjerven; Eric Bertolino; Zhengshan Chen; Stephen T. Smale; Susan Winandy; Harinder Singh

doi:10.1038/ni.1626

Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros

Damien Reynaud, Ignacio A. Demarco, Karen L. Reddy, Hilde Schjerven, Eric Bertolino, Zhengshan Chen, Stephen T. Smale, Susan Winandy, Harinder Singh

Research output: Contribution to journal › Article › peer-review

184 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	927-936
Number of pages	10
Journal	Nature Immunology
Volume	9
Issue number	8
DOIs	https://doi.org/10.1038/ni.1626
State	Published - Aug 2008
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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title = "Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros",

abstract = "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.",

author = "Damien Reynaud and Demarco, {Ignacio A.} and Reddy, {Karen L.} and Hilde Schjerven and Eric Bertolino and Zhengshan Chen and Smale, {Stephen T.} and Susan Winandy and Harinder Singh",

note = "Funding Information: We thank members of the Singh lab for suggestions and comments. Plasmids pEBB-Rag1 and pEBB-Rag2 were gifts from D.G. Schatz (Yale University); Pax5–/– pro–B cells were a gift from M. Busslinger (Research Institute of Molecular Pathology). Supported by the Irvington Institute Fellowship program of the Cancer Research Institute (I.A.D.), the Research Council of Norway (H.Sc.), the China Scholarship Council (Z.C.), the National Institutes of Health (R01 DK43726 to S.T.S.) and the Howard Hughes Medical Institute (H.Si.).",

year = "2008",

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doi = "10.1038/ni.1626",

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AU - Reynaud, Damien

AU - Demarco, Ignacio A.

AU - Reddy, Karen L.

AU - Schjerven, Hilde

AU - Bertolino, Eric

AU - Chen, Zhengshan

AU - Smale, Stephen T.

AU - Winandy, Susan

AU - Singh, Harinder

N1 - Funding Information: We thank members of the Singh lab for suggestions and comments. Plasmids pEBB-Rag1 and pEBB-Rag2 were gifts from D.G. Schatz (Yale University); Pax5–/– pro–B cells were a gift from M. Busslinger (Research Institute of Molecular Pathology). Supported by the Irvington Institute Fellowship program of the Cancer Research Institute (I.A.D.), the Research Council of Norway (H.Sc.), the China Scholarship Council (Z.C.), the National Institutes of Health (R01 DK43726 to S.T.S.) and the Howard Hughes Medical Institute (H.Si.).

PY - 2008/8

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N2 - 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.

AB - 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.

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Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros

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