DOT1L leaves its mark on adaptive immunity

Programming of gene expression is essential for cellular differentiation and function. This accomplished through a complex system epigenetic regulatory mechanisms that include post-translational modifications to the histones pack order DNA in nucleus. Among these modifications, mono-, di-, tri-methylation histone H3 at lysine 79 (H3K79me) are mediated by methyltransferase known as Disruptor telomeric silencing 1-like (DOT1L).1 DOT1L has been implicated diverse biological processes including embryonic development, damage response meiotic checkpoint control,2 promising drug target treatment mixed lineage leukemia (MLL)-rearranged where MLL fusion proteins recruit genes.2 both activation3 repression4 different contexts. Despite emerging roles various cell types diseases, its function immune was, until recently, largely uncharacterised. In two recent articles, studies Sebastian Scheer colleagues5 Liam Kealy colleagues6 define critical functions T B lymphocytes. Because deficiency leads lethality mice,7 utilise conditional knockout (KO) mouse models investigate specific populations et al. show an important regulator T-cell development crossing Cd4-Cre transgenic mice with Dot1lfl/fl generate lacking cells.5 These were prompted discovery same group identified function.8 Genetic cells resulted large reduction H3K79me2 CD4+ CD8+ cells. numbers markedly reduced thymus spleen exhibited increased apoptosis activation via receptor (TCR). therefore appears be central homeostasis. The authors also found spontaneous accumulation expressing marker CD44, but further analysis showed this phenotype was due lymphopenia, rather than intrinsic property DOT1L. Lymphopenia others underlie phenotypical changes can induced CD4-Cre-driven deletion transcription factor KLF2,9 indicating lymphopenia could responsible least some other transcriptional regulators. Naïve differentiate into several stable or semi-stable subsets helper (Th) after antigen encounter, interferon gamma (IFN-γ)-producing Th1 cells, interleukin (IL)-4/5/13-producing Th2 IL-17-producing Th17 cells.10 have elevated IFN-γ dependent on master T-bet. Differentiated normally resistant upregulation cell-associated genes programming,11, 12 findings from another key player regulation stability. Specifically, DOT1L-deficient able reprogrammed Th1-associated IFN-γ. primarily correlated activation, considered possibility might required promote regulators inhibit program. Indeed, highly expressed had more immunoregulatory Bach2 Foxp3 Th indicates potentially control repression negative Importantly, impair responses vivo, suggesting inhibition small molecule inhibitors viable therapeutic strategy limit such those observed allergic diseases. Appearing back-to-back issue Cell Reports independent study find role lymphocytes.6 employ strategies extensive range immunological challenges convincingly involvement humoral response. Using Mb1-Cre-driven Dot1lfl/fl, smaller spleens population bone marrow (BM) all To specifically delete mature crossed Cd23-Cre critically generation antigen-specific antibody immunisation. Strikingly, DOT1L-deficiency absence memory decreased plasma BM following influenza virus infection, needed effective GC reaction class-switched formation Th1- Th2-biased responses. Notably, T-cell-dependent T-cell-independent isotype-switched production. Neither proliferation nor altered fundamental physiological not causing immunity. Analysis transcriptome immunisation associated signaling migration, prompting localisation mice. BCL6 formation,13 during normal within follicles days still express BCL6, BCL6-expressing failed localise inside follicles. instead around outer edge follicle marginal zone spleen. Together, results al.5 al.6 provide thorough insight greatly expand our understanding how lymphocytes regulated. indicate displays degree specificity programs it controls, i.e. program antibody-producing regulating homing lymphoid tissue. Within programs, repress activate simultaneously. Defining exact way accomplishes will require investigation. It determine whether methylation-independent mediating functions.14 Finally, raise clinical questions extent which drugs designed treat malignant tumors affect healthy We thank Hospital Research Foundation (THRF) supporting Allergy Cancer Immunology Laboratory Centre Biology. DJT supported Fellowships THRF. declare no conflicts interest. Gökhan Cildir : Conceptualization; Writing-original draft; Writing-review & editing. Damon Tumes: