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

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Item Type:Preprint
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 Caganova, M. and Pardieck, I.N. and van den Brand, T. and Muhaimin, F.I. and van Welsem, T. and de Rink, I. and Song, J.Y. and de Wit, E. and Arens, R. and Rajewsky, K. 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 central role for the histone H3K79 methyltransferase DOT1L in controlling B cell differentiation. Naïve and activated murine B cells lacking Dot1L prematurely acquired plasma cell features and failed to establish germinal centers (GC) and normal humoral immune responses in vivo. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative (Myc) and pro-GC program (Bach2) and supports the expression of the H3K27 methyltransferase Ezh2, the catalytic component of Polycomb Repressor Complex 2 (PRC2). Thereby, DOT1L ensures PRC2-mediated repression of anti-proliferative and plasma cell differentiation program. Our findings show that DOT1L is a critical regulator of the core transcriptional and epigenetic landscape in B cells and establishes an epigenetic barrier warranting B cell naivety.
Keywords:B Cell Differentiation, DOT1L, EZH2, Epigenetics, Germinal Center B Cell, H3K79 Methylation, Plasma Cell
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory Press (U.S.A.)
Article Number:826370
Date:17 December 2019
Official Publication:https://doi.org/10.1101/826370

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