Rossol-Allison 2013

Dot1L heterozygous mice have a phenotype, an altered immune response, which may correlate with a reduction in H3K56ac and altered proliferation

Jessica Rossol-Allison

Kidney Institute and Department of Pathology & Laboratory Medicine, University of Kansas Medical Center

Dot1L (disruptor of telomere silencing 1 like) is a ubiquitously expressed histone methyltransferase that catalyzes the mono-, di-, and tri-methylation of lysine 79 on histone H3 (H3K79).  In mammals, H3K79 methylation regulates numerous biological processes, including genomic stability, transcription, differentiation, and proliferation.  Since Dot1L regulates such fundamental processes, it is not a surprise that Dot1L participates in transformation and tumorgenesis. We investigated the role Dot1L plays in proliferation and T-cell development.

We show that mice deficient in Dot1L have reduced levels of both H3K79 methylation and H3K56 acetylation (H3K56ac). H3K56ac is a mark of newly deposited histones and correlates with proliferation; which is consistent with an observed G0/G1 accumulation of Dot1L knock out embryonic fibroblasts.  We asked if a reduction of Dot1L in T cells, a cell type that can be induced to be highly proliferative upon antigen stimulation, would alter response to antigen. Since mice lacking both alleles of Dot1L die at E11, we analyzed CD4+ T-cell response to antigen in wild type (WT) and Dot1L heterozygous (Hets) mice 6-8 weeks of age.  We demonstrate that the CD4+ T cells from Hets display delayed activation and a different differentiation profile compared their WT littermates when stimulated with anti-CD3.  In conclusion, Dot1L heterozygous mice have a phenotype, an altered immune response, which may correlate with a reduction in H3K56ac and altered proliferation.