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The developmental dynamics and disease potential of random monoallelic gene expression

ABSTRACT: X-chromosome inactivation (XCI) in females and allelic exclusion of olfactory receptor or immunoglobulin loci, represent classic examples of random monoallelic expression (RME). RME of some single copy genes has also been reported, but the in vivo relevance of this remains unclear. Here we identify several hundred RME genes in clonal neural progenitor cell lines derived from embryonic stem cells. RME occurs during differentiation and once established, the monoallelic state can be highly stable. We show that monoallelic expression also occurs in vivo, in the absence of DNA sequence polymorphism, similarly to XCI. Several of the genes identified play important roles in development and have also been implicated in human autosomal dominant disorders. We propose that monoallelic expression of such genes contributes to the fine-tuning of the developmental regulatory pathways they control and in the context of a mutation, RME can predispose to loss of function in a proportion of cells and thus contribute to disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE54016 | GEO | 2014/02/27

SECONDARY ACCESSION(S): PRJNA234361

REPOSITORIES: GEO

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Project description: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.

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The developmental dynamics and disease potential of random monoallelic gene expression

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