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Allele-specific ATAC-seq across 16 neural progenitor cell clones

ABSTRACT: The two copies of a gene are canonically believed to be indistinguishable to the cell and are expressed in the same spatiotemporal manner in the absence of a loss-of-function mutation. The mechanisms by which cells break this symmetry and express a gene from only one of the two alleles of the diploid genome are of great interest. Monoallelic gene expression on the X-chromosome, at imprinted genes, and at olfactory receptor genes has been studied in detail and involves combinations of non-coding RNAs, DNA methylation, and histone modifications. Recently, random monoallelic gene expression (RME), in which a gene can be expressed from either or both alleles in a clonal manner, has been described across many cell types and disease-relevant genes. However little is known about how RME is established and regulated. Here we develop allele-specific ATAC-seq, a rapid and sensitive method for profiling active regulatory DNA allelically and genome-wide, and find that monoallelic chromatin accessibility is extensive, developmentally regulated, and epigenetically inherited. In clonal hybrid F1 murine neural progenitor cells, we find over 1800 monoallelically-accessible DNA elements across autosomes. Randomly monoallelic regulatory elements tend to be promoter-proximal and located at RME genes identified by RNA-seq. Following differentiation, they are highly stable across passages and bookmarked during mitosis. Most RME genes have monoallelic promoters, but surprisingly, the nearby enhancer landscape around RME genes is biallelic. This suggests that RME genes are regulated at the chromatin, not post-transcriptional level, and that highly localized promoter accessibility is the gatekeeper within a permissive regulatory landscape dictating monoallelic vs. biallelic expression. These randomly monoallelic promoters are biallelically accessible in a previous developmental state, indicating that one allele is randomly shut down during NPC specification. Furthermore, the distribution of active alleles for a subset of these randomly monoallelic regulatory elements across clones deviates from a binomial distribution, indicating a highly regulated, non-stochastic mechanism of establishment.

ORGANISM(S): Mus musculus

PROVIDER: GSE84646 | GEO | 2016/11/29

SECONDARY ACCESSION(S): PRJNA330723

REPOSITORIES: GEO

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Project description: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.

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Allele-specific ATAC-seq across 16 neural progenitor cell clones

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