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

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.

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8 + T cells

“…Although understanding the mechanisms in more detail will require further studies, the role of DOT1L in preventing premature differentiation and safeguarding the epigenetic identity is conserved in other lymphocyte subsets. In an independent study ( 75 ), we observed that loss of Dot1L in B cells also led to premature differentiation, perturbed repression of PRC2 targets, and a compromised humoral immune response. Therefore, DOT1L is emerging as a central epigenetic regulator of lymphocyte differentiation and functionality.…”

AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

“…These findings indicate that AF10 acts as a safeguarding mechanism for somatic cell identity by enabling higher order H3K79 methylation of somatic-specific genes. Presence of higher order H3K79 methylation may antagonize gene repression, thereby preventing silencing of somatic transcriptional programs upon OSKM expression (Stulemeijer et al, 2011)(Aslam et al, 2021). Alternatively, recent work points to a role for DOT1L in transcription initiation, and it will be interesting to investigate if AF10 plays a role in that process (Wu et al, 2020).…”