The term epigenetics was coined by Conrad Waddington in 1939, and recent advances in next generation sequencing technologies are now allowing genome-wide analyses of epigenetic regulation. A groundbreaking discovery in the field has been that a maternal or paternal allele of an autosomal gene can be randomly silenced, in a process termed random monoallelic expression (RMAE). In this way, RMAE is similar to X-inactivation, except that it is established at the level of a single gene as opposed to a whole chromosome. In 2007, it was shown that the expression of up to 10% of human genes, spanning a wide range of functions, may be influenced by RMAE. This raises the important question of the extent to which RMAE has been conserved across mammals. In a fascinating article by Andrew Chess and colleagues, published in this month’s issue of Genome Biology, this question has finally been answered.
Chess and colleagues first of all test whether genes are regulated by RMAE in other mammals by analysing genome-wide patterns of RMAE in mouse lines. Strikingly, they show that more than 15% of mouse genes surveyed are regulated by RMAE, and that there is a high level of conservation of RMAE between mouse and humans. These genes encode products with a wide variety of functions, just as has been shown for humans, suggesting that RMAE is not restricted to specific gene classes. They also find that genes affected by RMAE are distributed throughout the genome, and that active alleles are not influenced by the epigenetic state of adjacent loci. Once RMAE is established, allele specific expression is stably inherited through mitosis.
Crucially, they show that within a clone of cells, monoallelically expressed genes can be either maternally or paternally expressed, and are not influenced by the epigenetic state of neighboring cells. This means that the tissues of mammalian cells may resemble a patchwork quilt, with juxtaposed cells exhibiting different allelic expression patterns.
In one of their most interesting findings, they show that no gene classes are significantly enriched for RMAE in mouse, which is in contrast to previous work showing that in humans, transmembrane receptors are significantly enriched among genes displaying RMAE. This raises important questions about the differential functions of RMAE between mammalian species.
The results from Andrew Chess and colleagues strongly suggest that the regulatory mechanisms controlling RMAE were present in the last common ancestor of primates and rodents, which was thought to be roaming the earth 65-85 million years ago. It is clear that RMAE can cause differential expression between genetically identical cells, but it remains to be determined how RMAE is regulated, and what the adaptive advantage of RMAE is.
To read more about the results of Andrew Chess and colleagues, click here.