Abstract
Epigenetic mechanisms that cause maternally and paternally inherited alleles to be expressed differently in offspring have the potential to radically change our understanding of the mechanisms that shape disease susceptibility, phenotypic variation, cell fate, and gene expression. However, the nature and prevalence of these effects in vivo have been unclear and are debated. Here, I consider major new studies of epigenetic allelic effects in cell lines and primary cells and in vivo. The emerging picture is that these effects take on diverse forms, and this review attempts to clarify the nature of the different forms that have been uncovered for genomic imprinting and random monoallelic expression (RME). I also discuss apparent discrepancies between in vitro and in vivo studies. Importantly, multiple studies suggest that allelic effects are prevalent and can be developmental stage- and cell type-specific. I propose some possible functions and consider roles for allelic effects within the broader context of gene regulatory networks, cellular diversity, and plasticity. Overall, the field is ripe for discovery and is in need of mechanistic and functional studies.
Highlights
Epigenetic mechanisms that cause maternally and paternally inherited alleles to be expressed differently in offspring have the potential to radically change our understanding of the mechanisms that shape disease susceptibility, phenotypic variation, cell fate, and gene expression
The results of this study indicate that clonal random monoallelic expression (RME) is very rare in vivo, in agreement with the authors’ previous assessment of the field[16], but reveals that dynamic RME is frequent and more prevalent in human T cells than mouse fibroblasts
While we found that differential allelic expression is frequent in vivo, we found that very few autosomal genes exhibit evidence for clonal RME effects that are similar to random X-inactivation, which manifests as a negative allele correlation with our approach
Summary
Throughout this article, I have highlighted many exciting opportunities for discovery in this expanding field. I suggest that a deeper understanding of noncanonical imprinting and RME at the cellular level in vivo is needed, and I propose that some allelic effects might function to regulate the plasticity versus canalization of gene regulatory networks within a cell and shape cellular diversity within a population. New studies in the field have uncovered diverse forms of non-genetic allelic effects in vitro and in vivo and, when heterozygous mutations are present, these effects can shape the expression of mutated versus wild-type alleles at the cellular level, at least at the RNA level. Unlike imprinting, which impacts a defined subset of genes in the genome, RME appears to be a more general and dynamic property of gene expression, during development. The prevalence of clonal RME in vivo appears to be less than was initially thought from cell lines, but more studies are warranted. Competing interests The author declares that he has no competing interests
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