Epigenetic events regulating monoallelic gene expression

Abstract

In mammals, generally it is assumed that the genes inherited from each parent are expressed to similar levels. However, it is now apparent that in non-sex chromosomes, 6–10% of genes are selected for monoallelic expression. Monoallelic expression or allelic exclusion is established either in an imprinted (parent-of-origin) or a stochastic manner. The stochastic model explains random selection while the imprinted model describes parent-of-origin specific selection of alleles for expression. Allelic exclusion occurs during X chromosome inactivation, parent-of-origin expression of imprinted genes and stochastic monoallelic expression of cell surface molecules, clustered protocadherin (PCDH) genes. Mis-regulation or loss of allelic exclusion contributes to developmental diseases. Epigenetic mechanisms are fundamental players that determine this type of expression despite a homogenous genetic background. DNA methylation and histone modifications are two mediators of the epigenetic phenomena. The majority of DNA methylation is found on cytosines of the CpG dinucleotide in mammals. Several covalent modifications of histones change the electrostatic forces between DNA and histones modifying gene expression. Long-range chromatin interactions organize chromatin into transcriptionally permissive and prohibitive regions leading to simultaneous regulation of gene expression and repression. Non-coding RNAs (ncRNAs) are also players in regulating gene expression. Together, these epigenetic mechanisms fine-tune gene expression levels essential for normal development and survival. In this review, first we discuss what is known about monoallelic gene expression. Then, we focus on the molecular mechanisms that regulate expression of three monoallelically expressed gene classes: the X-linked genes, selected imprinted genes and PCDH genes.

• Allelic exclusion
• DNA methylation
• epigenetics
• gene regulation
• histone modifications
• monoallelic gene expression
• protocadherin
• X-chromosome inactivation

Declaration of interest

None of the authors have a conflict of interest. This work was funded by the Natural Science and Engineering Research Council of Canada grant RGPIN/372216-2011 and the Djavad Mowfaghian Foundation.