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Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis

Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with to failure to repress immune synapse genes linked to GC exit, which are a...

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Autores principales: Hatzi, Katerina, Geng, Huimin, Doane, Ashley S., Meydan, Cem, LaRiviere, Reed, Cardenas, Mariano, Duy, Cihangir, Shen, Hao, Vidal, Maria Nieves Calvo, Baslan, Timour, Mohammad, Helai P., Kruger, Ryan G., Shaknovich, Rita, Haberman, Ann M., Inghirami, Giorgio, Lowe, Scott W., Melnick, Ari M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294324/
https://www.ncbi.nlm.nih.gov/pubmed/30538335
http://dx.doi.org/10.1038/s41590-018-0273-1
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author Hatzi, Katerina
Geng, Huimin
Doane, Ashley S.
Meydan, Cem
LaRiviere, Reed
Cardenas, Mariano
Duy, Cihangir
Shen, Hao
Vidal, Maria Nieves Calvo
Baslan, Timour
Mohammad, Helai P.
Kruger, Ryan G.
Shaknovich, Rita
Haberman, Ann M.
Inghirami, Giorgio
Lowe, Scott W.
Melnick, Ari M.
author_facet Hatzi, Katerina
Geng, Huimin
Doane, Ashley S.
Meydan, Cem
LaRiviere, Reed
Cardenas, Mariano
Duy, Cihangir
Shen, Hao
Vidal, Maria Nieves Calvo
Baslan, Timour
Mohammad, Helai P.
Kruger, Ryan G.
Shaknovich, Rita
Haberman, Ann M.
Inghirami, Giorgio
Lowe, Scott W.
Melnick, Ari M.
author_sort Hatzi, Katerina
collection PubMed
description Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with to failure to repress immune synapse genes linked to GC exit, which are also direct targets of the BCL6 transcriptional repressor. We found that BCL6 directly binds and recruits LSD1, primarily to intergenic and intronic enhancers. Conditional deletion of Lsd1 suppressed GC hyperplasia caused by constitutive expression of Bcl6, and significantly delayed Bcl6-driven lymphomagenesis. Administration of LSD1 catalytic inhibitors had little effect on GC formation or GC derived lymphoma cells. Using a CRISPR/Cas9 domain screen we found instead that the LSD1 Tower domain was critical for LSD1 dependency in GC derived B cells. These results indicate an essential role of LSD1 in the humoral immune response, where it modulates enhancer function by forming repression complexes with BCL6.
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spelling pubmed-62943242019-06-10 Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis Hatzi, Katerina Geng, Huimin Doane, Ashley S. Meydan, Cem LaRiviere, Reed Cardenas, Mariano Duy, Cihangir Shen, Hao Vidal, Maria Nieves Calvo Baslan, Timour Mohammad, Helai P. Kruger, Ryan G. Shaknovich, Rita Haberman, Ann M. Inghirami, Giorgio Lowe, Scott W. Melnick, Ari M. Nat Immunol Article Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with to failure to repress immune synapse genes linked to GC exit, which are also direct targets of the BCL6 transcriptional repressor. We found that BCL6 directly binds and recruits LSD1, primarily to intergenic and intronic enhancers. Conditional deletion of Lsd1 suppressed GC hyperplasia caused by constitutive expression of Bcl6, and significantly delayed Bcl6-driven lymphomagenesis. Administration of LSD1 catalytic inhibitors had little effect on GC formation or GC derived lymphoma cells. Using a CRISPR/Cas9 domain screen we found instead that the LSD1 Tower domain was critical for LSD1 dependency in GC derived B cells. These results indicate an essential role of LSD1 in the humoral immune response, where it modulates enhancer function by forming repression complexes with BCL6. 2018-12-10 2019-01 /pmc/articles/PMC6294324/ /pubmed/30538335 http://dx.doi.org/10.1038/s41590-018-0273-1 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
Hatzi, Katerina
Geng, Huimin
Doane, Ashley S.
Meydan, Cem
LaRiviere, Reed
Cardenas, Mariano
Duy, Cihangir
Shen, Hao
Vidal, Maria Nieves Calvo
Baslan, Timour
Mohammad, Helai P.
Kruger, Ryan G.
Shaknovich, Rita
Haberman, Ann M.
Inghirami, Giorgio
Lowe, Scott W.
Melnick, Ari M.
Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis
title Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis
title_full Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis
title_fullStr Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis
title_full_unstemmed Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis
title_short Histone Demethylase LSD1 is required for Germinal Center formation and BCL6-driven lymphomagenesis
title_sort histone demethylase lsd1 is required for germinal center formation and bcl6-driven lymphomagenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294324/
https://www.ncbi.nlm.nih.gov/pubmed/30538335
http://dx.doi.org/10.1038/s41590-018-0273-1
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