Binary outcomes of enhancer activity underlie stable random monoallelic expression

We analyzed the natural killer (NK) cell receptor genes as in vivo genetic model to study random monoallelic gene expression (RME). These genes are expressed randomly, and largely monoallelically, in subsets of NK cells to generate a repertoire of specificities. We found that enhancers directly controlled the probability of expression of both RME and related, broadly expressed genes. We present an analysis of the accessibility (ATAC-seq) and both active and repressive histone modifications of elements associated with both expressed and silent alleles of the NK receptor genes in primary cells. The goals of this study were to assess the chromatin state of the silent and active alleles of the monoallelically expressed natural killer (NK) cell receptor genes. Overall design: We examined chromatin accessibility and histone modifications in primary NK cells sorted to be homogenous with respect to allelic expression status of the variegated/monoallelically expressed NK receptor genes, Klrc1/Nkg2a, Klrk1/Nkg2d and Klra7/Ly49g. ATAC-seq data were aligned to the mm10 genome, or separately aligned to a SNP-masked genome and allele-informative reads were binned into B6 (genome1) or BALB/c (genome2) .bam files and processed to .bw files. CUT&RUN files were all aligned to the mm10 genome. Funding source for Stefan Muljo: Intramural Research Program of NIH, NIAID.