Silencing and Nuclear Repositioning of the λ5 Gene Locus at the Pre-B Cell Stage Requires Aiolos and OBF-1
The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a blo...
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Published in | PloS one Vol. 3; no. 10; p. e3568 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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Abstract | The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes λ5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the λ5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function. |
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AbstractList | The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes
λ5
and
VpreB
, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the
λ5
gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function. The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes λ5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the λ5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function. |
Author | Carotta, Sebastian Cao, Chun Karnowski, Alexander Martensson, Inga-Lill Skok, Jane A. Matthias, Patrick Matthias, Gabriele Corcoran, Lynn M. |
AuthorAffiliation | 3 Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge, United Kingdom 5 New York University School of Medicine, New York, New York, United States of America National Institute on Aging, United States of America 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia 1 Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland 4 Department of Immunology and Molecular Pathology, University College London, London, United Kingdom |
AuthorAffiliation_xml | – name: 3 Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge, United Kingdom – name: 4 Department of Immunology and Molecular Pathology, University College London, London, United Kingdom – name: National Institute on Aging, United States of America – name: 1 Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland – name: 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia – name: 5 New York University School of Medicine, New York, New York, United States of America |
Author_xml | – sequence: 1 givenname: Alexander surname: Karnowski fullname: Karnowski, Alexander – sequence: 2 givenname: Chun surname: Cao fullname: Cao, Chun – sequence: 3 givenname: Gabriele surname: Matthias fullname: Matthias, Gabriele – sequence: 4 givenname: Sebastian surname: Carotta fullname: Carotta, Sebastian – sequence: 5 givenname: Lynn M. surname: Corcoran fullname: Corcoran, Lynn M. – sequence: 6 givenname: Inga-Lill surname: Martensson fullname: Martensson, Inga-Lill – sequence: 7 givenname: Jane A. surname: Skok fullname: Skok, Jane A. – sequence: 8 givenname: Patrick surname: Matthias fullname: Matthias, Patrick |
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ContentType | Journal Article |
Copyright | 2008 Karnowski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Karnowski et al. 2008 |
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Notes | Conceived and designed the experiments: AK JAS PM. Performed the experiments: AK CC GM JAS. Analyzed the data: AK CC GM SC LC ILM JAS PM. Contributed reagents/materials/analysis tools: AK CC GM SC LC ILM JAS. Wrote the paper: AK PM. |
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SubjectTerms | Biomedical research Bone marrow Cell activation Cell cycle Chains Chromatin Deoxyribonucleic acid Deregulation DNA Fibroblasts Gene expression Genes Genetics and Genomics/Gene Expression Genetics and Genomics/Gene Function Immunoglobulins Immunology Immunology/Genetics of the Immune System Immunology/Leukocyte Development Immunology/Leukocyte Signaling and Gene Expression Laboratories Light Lymphocytes Lymphocytes B Medical research Mice Proteins Rodents Spleen Transcription Transcription factors |
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Title | Silencing and Nuclear Repositioning of the λ5 Gene Locus at the Pre-B Cell Stage Requires Aiolos and OBF-1 |
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