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Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, Düsseldorf, Germany
The clonal distribution and stable expression of killer cell Ig-like receptor (KIR) genes is epigenetically regulated. To assess the epigenetic changes that occur during hemopoietic development we examined DNA methylation and chromatin structure of the KIR locus in early hemopoietic progenitor cells and major lymphocyte lineages. In hemopoietic progenitor cells, KIR genes exhibited the major hallmarks of epigenetic repression, which are dense DNA methylation, inaccessibility of chromatin to Micrococcus nuclease digest, and a repressive histone signature, characterized by strong H3K9 dimethylation and reduced H4K8 acetylation. In contrast, KIR genes of NK cells showed active histone signatures characterized by absence of H3K9 dimethylation and presence of H4K8 acetylation. Histone modifications correlated well with the competence of different lymphocyte lineages to express KIR; whereas H4K8 acetylation was high in NK and CD8+ T cells, it was almost absent in CD4+ T cells and B cells and, in the latter case, replaced by H3K9 dimethylation. In KIR-competent lineages, active histone signatures were also observed in silent KIR genes and in this case found in combination with dense DNA methylation of the promoter and nearby regions. The study suggests a two-step model of epigenetic regulation in which lineage-specific acquisition of euchromatic histone marks is a prerequisite for subsequent gene-specific DNA demethylation and expression of KIR genes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Deutsche Forschungsgemeinschaft to M.U. (UH 91/2-1), the Medical Faculty of the University of Düsseldorf to S.S. and M.U., and the Deutsche Krebshilfe to M.U. within the research network "Immune therapy of malignant disease by transplantation of allogeneic hematopoietic stem cells."
2 Address correspondence and reprint requests to Dr. Markus Uhrberg, Heinrich Heine University, University Clinic of Düsseldorf, Building 14.80, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail address: uhrberg{at}itz.uni-duesseldorf.de
3 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; HPC, hemopoietic progenitor cell; RAI, relative accessibility index; ChIP, chromatin immunoprecipitation, RUNX, runt-related protein.
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