School of Mathematics and Statistics - Research Publications

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Author: Allan, Rhys × End date: 2019 × Start date: 2017 ×

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    A non-canonical function of Ezh2 preserves immune homeostasis
    Vasanthakumar, A ; Xu, D ; Lun, ATL ; Kueh, AJ ; van Gisbergen, KPJM ; Iannarella, N ; Li, X ; Yu, L ; Wang, D ; Williams, BRG ; Lee, SCW ; Majewski, IJ ; Godfrey, DI ; Smyth, GK ; Alexander, WS ; Herold, MJ ; Kallies, A ; Nutt, SL ; Allan, RS (WILEY, 2017-04)
    Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis. T-cell-specific depletion of Ezh2 induces a pronounced expansion of natural killer T (NKT) cells, although Ezh2-deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF, leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2-deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin-independent function of Ezh2 that impacts on the development of the immune system.
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    Genome-wide analysis reveals no evidence of trans chromosomal regulation of mammalian immune development
    Johanson, TM ; Coughlan, HD ; Lun, ATL ; Bediaga, NG ; Naselli, G ; Garnham, AL ; Harrison, LC ; Smyth, GK ; Allan, RS ; Barsh, GS (PUBLIC LIBRARY SCIENCE, 2018-06)
    It has been proposed that interactions between mammalian chromosomes, or transchromosomal interactions (also known as kissing chromosomes), regulate gene expression and cell fate determination. Here we aimed to identify novel transchromosomal interactions in immune cells by high-resolution genome-wide chromosome conformation capture. Although we readily identified stable interactions in cis, and also between centromeres and telomeres on different chromosomes, surprisingly we identified no gene regulatory transchromosomal interactions in either mouse or human cells, including previously described interactions. We suggest that advances in the chromosome conformation capture technique and the unbiased nature of this approach allow more reliable capture of interactions between chromosomes than previous methods. Overall our findings suggest that stable transchromosomal interactions that regulate gene expression are not present in mammalian immune cells and that lineage identity is governed by cis, not trans chromosomal interactions.