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Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation

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Item Type:Article
Title:Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation
Creators Name:Aslam, M.A. and Alemdehy, M.F. and Kwesi-Maliepaard, E.M. and Muhaimin, F.I. and Caganova, M. and Pardieck, I.N. and van den Brand, T. and van Welsem, T. and de Rink, I. and Song, J.Y. and de Wit, E. and Arens, R. and Jacobs, H. and van Leeuwen, F.
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 role for the histone H3K79 methyltransferase DOT1L in controlling B-cell differentiation. Mouse B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells in which Dot1L was deleted showed aberrant differentiation and prematurely acquired plasma cell characteristics. Similar results were obtained when DOT1L was chemically inhibited in mature B cells in vitro. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L indirectly supports the repression of an anti-proliferative plasma cell differentiation program by maintaining the repression of Polycomb Repressor Complex 2 (PRC2) targets. Our findings show that DOT1L is a key 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.
Keywords:B-Cell Differentiation, DOT1L, Germinal Center B Cell, Plasma Cell, PRC2, Animals, Mice
Source:EMBO Reports
ISSN:1469-221X
Publisher:EMBO Press
Volume:22
Number:2
Page Range:e51184
Date:3 February 2021
Official Publication:https://doi.org/10.15252/embr.202051184
PubMed:View item in PubMed
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https://edoc.mdc-berlin.de/18613/Preprint version

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