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The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development

Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors involved in MBC differentiation are poorly defined. Here, by single-cell RNA-seq analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. U...

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Detalles Bibliográficos
Autores principales: Laidlaw, Brian J., Duan, Lihui, Xu, Ying, Vazquez, Sara E., Cyster, Jason G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442689/
https://www.ncbi.nlm.nih.gov/pubmed/32601467
http://dx.doi.org/10.1038/s41590-020-0713-6
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author Laidlaw, Brian J.
Duan, Lihui
Xu, Ying
Vazquez, Sara E.
Cyster, Jason G.
author_facet Laidlaw, Brian J.
Duan, Lihui
Xu, Ying
Vazquez, Sara E.
Cyster, Jason G.
author_sort Laidlaw, Brian J.
collection PubMed
description Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors involved in MBC differentiation are poorly defined. Here, by single-cell RNA-seq analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. Using an inducible Crispr/Cas9 screening approach we identified the hematopoietically expressed homeobox gene Hhex as a transcription factor regulating MBC differentiation. The co-repressor Tle3 was also identified in the screen and was found to interact with Hhex to promote MBC development. Bcl-6 directly repressed Hhex in GC B cells. Reciprocally, Hhex-deficient MBCs exhibited derepressed Bcl6 and reduced expression of Bcl-6-repressed Bcl2. Overexpression of Bcl-2 was able to rescue MBC differentiation in Hhex-deficient cells. We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation. These findings establish an important role for Hhex-Tle3 in regulating the transcriptional circuitry governing MBC differentiation.
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spelling pubmed-74426892020-12-29 The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development Laidlaw, Brian J. Duan, Lihui Xu, Ying Vazquez, Sara E. Cyster, Jason G. Nat Immunol Article Memory B cells (MBCs) are essential for long-lived humoral immunity. However, the transcription factors involved in MBC differentiation are poorly defined. Here, by single-cell RNA-seq analysis, we identified a population of germinal center (GC) B cells in the process of differentiating into MBCs. Using an inducible Crispr/Cas9 screening approach we identified the hematopoietically expressed homeobox gene Hhex as a transcription factor regulating MBC differentiation. The co-repressor Tle3 was also identified in the screen and was found to interact with Hhex to promote MBC development. Bcl-6 directly repressed Hhex in GC B cells. Reciprocally, Hhex-deficient MBCs exhibited derepressed Bcl6 and reduced expression of Bcl-6-repressed Bcl2. Overexpression of Bcl-2 was able to rescue MBC differentiation in Hhex-deficient cells. We also identified Ski as an Hhex-induced transcription factor involved in MBC differentiation. These findings establish an important role for Hhex-Tle3 in regulating the transcriptional circuitry governing MBC differentiation. 2020-06-29 2020-09 /pmc/articles/PMC7442689/ /pubmed/32601467 http://dx.doi.org/10.1038/s41590-020-0713-6 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Laidlaw, Brian J.
Duan, Lihui
Xu, Ying
Vazquez, Sara E.
Cyster, Jason G.
The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
title The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
title_full The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
title_fullStr The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
title_full_unstemmed The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
title_short The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development
title_sort transcription factor hhex cooperates with the corepressor tle3 to promote memory b cell development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442689/
https://www.ncbi.nlm.nih.gov/pubmed/32601467
http://dx.doi.org/10.1038/s41590-020-0713-6
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