Article series: Modes of transcriptional regulation

Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation

Journal name:
Nature Reviews Genetics
Volume:
16,
Pages:
653–664
Year published:
DOI:
doi:10.1038/nrg3888
Published online

Abstract

Random monoallelic expression (RME) of genes represents a striking example of how stochastic molecular processes can result in cellular heterogeneity. Recent transcriptome-wide studies have revealed both mitotically stable and cell-to-cell dynamic forms of autosomal RME, with the latter presumably resulting from burst-like stochastic transcription. Here, we discuss the distinguishing features of these two forms of RME and revisit literature on their nature, pervasiveness and regulation. Finally, we explore how RME may contribute to phenotypic variation, including the incomplete penetrance and variable expressivity often seen in genetic disease.

At a glance

Figures

  1. Modes of monoallelic gene expression.
    Figure 1: Modes of monoallelic gene expression.

    Schematic figure illustrating cell- and population-level features across classes of monoallelic gene expression. The left panels show possible single-cell states, with transcription (denoted by arrows) occurring at the maternal (mat) and/or the paternal (pat) gene copies. The right panels illustrate allelic expression within populations of cells (represented by circles), colour-coded by their allelic expression. The coloured brackets signify clonally related cells in which fixed monoallelic or biallelic regulation has been propagated through cellular division. The arrow and bar beneath each cell cluster show the allelic expression as it would be detected over whole populations. The expected patterns are described for genomic imprinting (part a), random X-chromosome (ChrX) inactivation (part b), allelic exclusion (antigen and olfactory receptors; part c), widespread fixed autosomal random monoallelic expression (aRME) (part d) and dynamic aRME (part e). Note that imprinted expression can be maternal as well as paternal, often appears in gene clusters and can be lost in some tissues105, 106.

  2. Causes of fixed and dynamic aRME.
    Figure 2: Causes of fixed and dynamic aRME.

    a | The initiation event for fixed autosomal random monoallelic gene expression (aRME) is either the silencing of one allele from a previously biallelically expressed gene or the activation of a single allele from a previously silent gene.In the latter case, the allele activation could be coupled with a feedback mechanism that prevents activation of the second allele; alternatively, a limited time-window of low-probability initiation could achieve high frequencies of cells with single-allele expression. As the allelic choice of fixed aRME is mitotically transferred, regulatory modifications must be tightly associated with the alleles in cis. Note that the initial modification does not have to be same as the long-term propagated one. b | Transcription occurs in bursts of RNA molecules from each allele, so that over time (x-axis) both alleles have a certain probability to initiate transcription and produce a set of molecules. For most autosomal genes, both alleles have equal probability of initiating transcription of a given gene, related to its cell-type specific expression level. The exact timing of the allelic bursts is stochastic, and here illustrated as idealized waves of maternal (red) and paternal (blue) RNA copy numbers. Coupled with RNA degradation, such episodic allelic output leads to periods in which the accumulated RNA present in the cell (summarized in the bottom panel) is maternal, paternal, biallelic or not present. The gene's burst frequency, the number of molecules it produces per burst episode and its RNA-degradation rate dictate the shape of RNA distribution following a transcriptional event and thus the probability of the cell having monoallelic or biallelic expression at any given time of inquiry. Dynamic aRME is thus a consequence of stochastic allelic expression, which represents a ground state of gene expression in single cells.

  3. Models for phenotypic consequences of aRME.
    Figure 3: Models for phenotypic consequences of aRME.

    For cells carrying two inequivalent alleles, cellular functionality with respect to an encoded gene product may vary according to random monoallelic gene expression (RME). a | For fixed autosomal RME (aRME), this could result in stochastic phenotypic patchiness, as any daughter cells after the random allelic fixation would express one of two dissimilar gene copies. Similarly, cell variability could result from a dose effect (that is, expression of one versus two alleles in different lineages). b | Dynamic aRME of inequivalent alleles could produce temporal stochastic phenotypic effects, which are more likely to be pronounced in smaller populations of founder cells (for example, stem or progenitor cells) and for processes that are dependent on precise concentrations of functional proteins within a short developmental time-window. Consequently, genes with infrequent allelic bursts would be more prone to producing such effects. c | The phenotypic effects in founder cells extended to include concepts of intracellular allelic recessivity and dominance. If the mutant allele (B) is recessive, the dysfunctional allelic product can be compensated for by expression from the intact allele (A) (shown as 'Allele A overrides B'). By contrast, if the mutant trait is dominant, it causes a deleterious effect even if the normal allele is present, which increases the probability that phenotypic effects will appear (shown as 'Allele B overrides A').

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  1. Ludwig Institute for Cancer Research, Box 240, and the Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.

    • Björn Reinius &
    • Rickard Sandberg

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  • Björn Reinius

    Björn Reinius received his Ph.D. in molecular biology from Uppsala University, Sweden, and earned a double degree in chemistry and biology from the same university. He has a particular interest in the regulation and evolution of dosage compensation and allele-specific gene expression. His current research involves experimental and computational analyses of allelic expression patterns in single cells. He is a postdoctoral fellow in Rickard Sandberg's laboratory at the Karolinska Institutet, Stockholm, Sweden.

  • Rickard Sandberg

    Rickard Sandberg is an associate professor at the Karolinska Institutet, Stockholm, Sweden, leading a research group focusing on understanding the mechanisms of gene regulation through improved measurement of gene expression at single-cell resolution. His laboratory is developing cutting-edge experimental and computational methods that are being used to address issues such as lineage commitment of stem and progenitor cells and cell-type diversity in adult tissues. Before starting his laboratory, he was a postdoctoral research scientist in Christopher Burge's laboratory at Massachusetts Institute of Technology, Cambridge, USA, and before that he obtained a Ph.D. at the Karolinska Institutet. Rickard Sandberg's homepage.

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