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

Aslam, M.A.; Alemdehy, M.F.; Kwesi-Maliepaard, E.M.; Muhaimin, F.I.; Caganova, M.; Pardieck, I.N.; van den Brand, T.; van Welsem, T.; de Rink, I.; Song, J.Y.; de Wit, E.; Arens, R.; Jacobs, H.; van Leeuwen, F.

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:	Aslam, M.A. ORCID: https://orcid.org/0000-0003-1905-2583, Alemdehy, M.F. ORCID: https://orcid.org/0000-0002-7936-0652, Kwesi-Maliepaard, E.M. ORCID: https://orcid.org/0000-0001-9658-1935, Muhaimin, F.I., Caganova, M. ORCID: https://orcid.org/0000-0002-4576-6574, Pardieck, I.N., van den Brand, T., van Welsem, T., de Rink, I., Song, J.Y., de Wit, E., Arens, R., Jacobs, H. ORCID: https://orcid.org/0000-0001-6227-9850 and van Leeuwen, F. ORCID: https://orcid.org/0000-0002-7267-7251
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 / Wiley
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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