Lineage-Specific Transition of Histone Signatures in the Killer Cell Ig-Like Receptor Locus from Hematopoietic Progenitor to NK Cells

Abstract

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 transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element

“…This is supported by a recent study showing that the distal promoter is densely methylated in both KIR-positive and KIR-negative cells. 45 The overexpression of c-Myc in NK92 cells may force high levels of transcriptional initiation from the distal promoter and generate distal transcripts over time despite methylation of CpG islands within the proximal promoter. Single-stranded distal mRNA transcripts could then complex with DNA demethylase enzymes, leading to sequencespecific DNA demethylation of KIR promoters over time.…”

KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression

“…KIR genes are epigenetically regulated with histone acetylation of the KIR locus followed by demethylation of the KIR promotors. 35,36 Recently, models have been proposed to account for the regulation of KIR and Ly49 expression at the genetic level. 37 These models imply that intergenic RNAs produced via probabilistic mechanisms control the selective activation or silencing of KIR alleles.…”

H3K9 Methylation Regulates Growth and Development in Aspergillus fumigatus

“…H3K9 methylation regulates developmental processes in many species. Examples include the regulation of stem cell pluripotency via expression of the HOXA cluster (5), regulation of KIR gene expression in natural killer cells (37), vulval development in Caenorhabditis elegans (4), and pleiotropic regulation of Drosophila development (52).…”