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

Weizheng Liang,Guipeng Li,Shaojie Zhou,Chi Tian,Bernhard Schaefke,Xudong Zou

doi:10.3389/fcell.2021.717555

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.

Highlights

Protein-coding information stored in DNA is first transcribed to mRNA and translated into polypeptide chains
Our study provides a detailed portrait of allelic gene expression including monoallelic genes, across multiple tissues/cell lines in a hybrid mouse model and allelic chromatin accessibility patterns in two different cell lines
We identified six autosomal monoallelic genes with the active allele being identical in all eight tissues, resembling the patterns found for known imprinted genes and likely to be novel candidates of imprinted genes

Summary

Introduction

Protein-coding information stored in DNA is first transcribed to mRNA and translated into polypeptide chains. With two alleles sharing the same trans environment, allelic differences in the F1 hybrid can be directly interpreted as cisregulatory divergence (Gao et al, 2015; Hou et al, 2015; Xiao et al, 2016) By comparing these allelic-specific variations with the differences between parental strains or species, the transcomponent of gene expression differences can be estimated (Wittkopp et al, 2004, 2008; Goncalves et al, 2012; Wong et al, 2017). The interplay of these two kinds of elements shaping the regulatory patterns of gene expression divergence across tissues in mammals has not been fully understood

Methods

Results

Conclusion