Systematic Analysis of Monoallelic Gene Expression and Chromatin Accessibility Across Multiple Tissues in Hybrid Mice

Abstract

In diploid eukaryotic organisms, both alleles of each autosomal gene are usually assumed to be simultaneously expressed at similar levels. However, some genes can be expressed preferentially or strictly from a single allele, a process known as monoallelic expression. Classic monoallelic expression of X-chromosome-linked genes, olfactory receptor genes and developmentally imprinted genes is the result of epigenetic modifications. Genetic-origin-dependent monoallelic expression, however, is caused by cis-regulatory differences between the alleles. There is a paucity of systematic study to investigate these phenomena across multiple tissues, and the mechanisms underlying such monoallelic expression are not yet fully understood. Here we provide a detailed portrait of monoallelic gene expression across multiple tissues/cell lines in a hybrid mouse cross between the Mus musculus strain C57BL/6J and the Mus spretus strain SPRET/EiJ. We observed pervasive tissue-dependent allele-specific gene expression: in total, 1,839 genes exhibited monoallelic expression in at least one tissue, and 410 genes in at least two tissues. Among these 88 are monoallelic genes with different active alleles between tissues, probably representing genetic-origin-dependent monoallelic expression. We also identified six autosomal monoallelic genes with the active allele being identical in all eight tissues, which are likely novel candidates of imprinted genes. To depict the underlying regulatory mechanisms at the chromatin layer, we performed ATAC-seq in two different cell lines derived from the F1 mouse. Consistent with the global expression pattern, cell-type dependent monoallelic peaks were found, and a higher proportion of C57BL/6J-active peaks were observed in both cell types, implying possible species-specific regulation. Finally, only a small part of monoallelic gene expression could be explained by allelic differences in chromatin organization in promoter regions, suggesting that other distal elements may play important roles in shaping the patterns of allelic gene expression across tissues.