Abstract
Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). The extent and nature of RME has been the subject of debate. Here we investigate the expression of several candidate RME genes in F1 hybrid mouse cells before and after differentiation, to define how they become persistently, monoallelically expressed. Clonal monoallelic expression is not present in embryonic stem cells, but we observe high frequencies of monoallelism in neuronal progenitor cells by assessing expression status in more than 200 clones. We uncover unforeseen modes of allelic expression that appear to be gene-specific and epigenetically regulated. This non-canonical allelic regulation has important implications for development and disease, including autosomal dominant disorders and opens up therapeutic perspectives.
Highlights
Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME)
In order to assess the frequency with which these genes show RME, we differentiated male or female hybrid (129/Sv x Castaneus) mouse ES cells (ESCs) into neural progenitor cells (NPC), as previously described[11,21] (Fig. 1 and Supplementary Fig. 1)
The analysis of a very high number (>200) of NPC clones revealed that genes previously identified as RME display one or several modalities of allelic expression, with different degrees of allelic imbalance
Summary
Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). RME genes were identified through numerous genome-wide allele-specific analyses of gene expression in single-cell derived clones from hybrid cell lines[6,7,8,9,10,11,12,13,14] These studies showed that some genes can be expressed monoallelically from the maternal or paternal allele, or biallelically, and that these expression patterns are inherited during cell division. These RME genes[15] belong to a wide range of gene ontologies and are enriched in cell surface receptors, developmental regulators, and are often associated with human autosomal dominant diseases[6,10,11]. There have been some efforts to identify RME in vivo[11,19], transient and stable RME cannot be readily distinguished at the single-cell level
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