Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation
EMBO Reports, vol. 22, pp. e51184
Abstract
Abstract Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B cell fate remain unclear. Here we identified a central role for the histone H3K79 methyltransferase DOT1L in controlling B cell differentiation. Murine B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo . In vitro , activated B cells showed aberrant differentiation and prematurely acquired plasma cell features. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L supports the repression of an anti-proliferative, plasma cell differentiation program by maintaining expression of the H3K27 methyltransferase Ezh2 , the catalytic component of Polycomb Repressor Complex 2 (PRC2). Our findings show that DOT1L is a central modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B cell naivety and GC B cell differentiation.
Authors 15
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Bahauddin Zakariya University · The Netherlands Cancer Institute
Affiliation as printed
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, 60800 Multan, Pakistan
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
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The Netherlands Cancer Institute
Affiliation as printed
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Max Delbrück Center · The Netherlands Cancer Institute
Affiliation as printed
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
Division of Tumor Biology and Immunology Netherlands Cancer Institute Amsterdam The Netherlands
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Max Delbrück Center · Leiden University Medical Center
Affiliation as printed
Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Max‐Delbrück‐Center for Molecular Medicine Berlin Germany
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Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute The Netherlands
Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Gene Regulation, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Genome Core Facility, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Genome Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Division of Experimental Animal Pathology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Division of Experimental Animal Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Gene Regulation, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
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Max Delbrück Center · The Netherlands Cancer Institute
Affiliation as printed
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Heinz Jacobs corresponding
Amsterdam UMC Location University of Amsterdam · The Netherlands Cancer Institute · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Division of Tumor Biology and Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
Department of Medical Biology, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Fred van Leeuwen corresponding
Amsterdam UMC Location University of Amsterdam · The Netherlands Cancer Institute · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Medical Biology, Amsterdam UMC, location AMC, UvA, 1105 AZ Amsterdam, The Netherlands
Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands