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

• Published in: EMBO reports Vol. 22; no. 2; pp. e51184 - n/a
• Main Authors: Aslam, Muhammad Assad, Alemdehy, Mir Farshid, Kwesi-Maliepaard, Eliza Mari, Muhaimin, Fitriari Izzatunnisa, Caganova, Marieta, Pardieck, Iris N, van den Brand, Teun, van Welsem, Tibor, de Rink, Iris, Song, Ji-Ying, de Wit, Elzo, Arens, Ramon, Jacobs, Heinz, van Leeuwen, Fred
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-02-2021; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Animals; B-Lymphocytes - cytology; B‐cell differentiation; Cell Differentiation; Cell fate; Differentiation (biology); DOT1L; EMBO09; EMBO19; EMBO31; Epigenesis, Genetic; Epigenetics; Gene silencing; germinal center B cell; Germinal centers; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histones; Histones - genetics; Histones - metabolism; Immune response (humoral); Lymphocytes B; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Plasma; plasma cell; Plasma cells; Polycomb group proteins; PRC2; Regulators; Transcription; B-cell differentiation; PRC2; plasma cell; germinal center B cell; DOT1L
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202051184

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.
SYNOPSIS
The histone H3K79 methyltransferase DOT1L plays a central role in B cell development and differentiation. DOT1L maintains B cells naivety by orchestrating critical transcriptional and epigenetic regulators.
DOT1L is essential for the formation of germinal center B cells.
DOT1L prevents premature differentiation of naïve B cells towards plasma cells.
DOT1L contributes to the repression of PRC2 target genes.
Graphical Abstract
The histone H3K79 methyltransferase DOT1L plays a central role in B cell development and differentiation. DOT1L maintains B cells naivety by orchestrating critical transcriptional and epigenetic regulators.