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

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

doi:10.1101/826370

bioRxiv · 10.1101/826370

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

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

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Abstract

Differentiation of naive 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.

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Aslam, M. A., Alemdehy, M. F., Kwesi-Maliepaard, E. M., Caganova, M., Pardieck, I. N., van den Brand, T., Muhaimi, F. I., van Welsem, T., de Rink, I., Song, J.-Y., de Wit, E., Arens, R., Rajewsky, K., Jacobs, H., van Leeuwen, F.. 2019-10-31. Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation. https://doi.org/10.1101/826370

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