Fred Van Leeuwen - Targeting epigenetic regulation at the core: the histone methyltransferase DOT1L in cytotoxic T cells

Fred Van Leeuwen (Netherlands Cancer Institute)

19 mai 2022

intervenant : Fred van Leeuwen

Infos pratiques

12h00 - 13h00
Salle Rosalind Franklin et en visio
Professionnel de recherche
Accès mobilité réduite

The Van Leeuwen lab studies mechanisms and principles of epigenetic regulation, using innovative proteomic, genetic, and (epi)genomics approaches. They take advantage of yeast as a powerful model system and, in parallel, they are developing tools in human cells to translate their findings to mammals. They use mouse models to unravel the role of chromatin-based mechanisms in T- and B-cell development and cancer.

His lab has been studying the histone methyltransferase DOT1L for many years. This enzyme methylates lysine 79 of histone H3 (H3K79) along gene bodies and influences gene regulation, DNA damage response and oncogenic transformation in mammals. Using a combination of yeast genetics, proteomics and modeling, they have obtained a comprehensive picture of the mechanisms of action and regulation of DOT1L, including during lymphomagenesis. Their recent studies show that DOT1L plays a critical role in normal T and B cell differentiation, and their research now focusses on understanding how DOT1L affects T cell function and how this knowledge can be used to modulate the adaptive immune system.

Group website:

Invité par Julie Cocquet

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Recent publications

Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation.  Aslam MA, Alemdehy MF, Kwesi-Maliepaard EM, Muhaimin FI, Caganova M, Pardieck IN, van den Brand T, van Welsem T, de Rink I, Song JY, de Wit E, Arens R, Jacobs H, van Leeuwen F. EMBO Rep. 2021

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells. Kwesi-Maliepaard EM, Aslam MA, Alemdehy MF, van den Brand T, McLean C, Vlaming H, van Welsem T, Korthout T, Lancini C, Hendriks S, Ahrends T, van Dinther D, den Haan JMM, Borst J, de Wit E, van Leeuwen F, Jacobs H. Proc Natl Acad Sci U S A. 2020  

Inhibition of transcription leads to rewiring of locus-specific chromatin proteomes.  Poramba-Liyanage DW, Korthout T, Cucinotta CE, van Kruijsbergen I, van Welsem T, El Atmioui D, Ovaa H, Tsukiyama T, van Leeuwen F. Genome Res. 2020

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma.  Vlaming H, McLean CM, Korthout T, Alemdehy MF, Hendriks S, Lancini C, Palit S, Klarenbeek S, Kwesi-Maliepaard EM, Molenaar TM, Hoekman L, Schmidlin TT, Altelaar AM, van Welsem T, Dannenberg JH, Jacobs H, van Leeuwen F. EMBO J. 2019

 Dot1 promotes H2B ubiquitination by a methyltransferase-independent mechanism. van Welsem T, Korthout T, Ekkebus R, Morais D, Molenaar TM, van Harten K, Poramba-Liyanage DW, Sun SM, Lenstra TL, Srivas R, Ideker T, Holstege FCP, van Attikum H, El Oualid F, Ovaa H, Stulemeijer IJE, Vlaming H, van Leeuwen F. Nucleic Acids Res. 2018