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.

Translating RNA sequencing into clinical diagnostics: opportunities and challenges

“…Allele-specific expression. Allele-specific expression (ASE) can arise through multiple mechanisms, including genetic imprinting, X-chromosome inactivation and allele-specific transcription 36 ; in some cases, ASE has been associated with predisposition to disease 37,38 . One…”

The genetics of pubertal timing in the general population

“…Mammalian embryos may have sex-specific gene expression before random X-inactivation (33), which may have later-life effects on gene expression. In addition, 6–10% of autosomal genes are monoallelically expressed (59), and in these cases, parent-of-origin effects such as at MKRN3 can occur where a variant is expressed when it comes from one parent and not the other.…”

Genetic modes of epigenetic modification and its research progress

“…这些来自母代的ncRNA还 可能参与将表观遗传信息传递到子代的过程. 有研 究发现在植物和线虫中, ncRNA分子可以穿梭于细胞 之间(包括体细胞和生殖细胞) [32,36] [37,38] . 基因组印记对发育具有重要 的调控作用, 印记基因的异常不仅影响胚胎发育, 还 可导致胎儿出生后发育的异常, 甚至引起癌症的发 生 [38] .…”

“…X染色体失活(X chromosome inactivation, XCI) 是哺乳动物雌性个体中实现X染色体的剂量补偿效 应(dosage compensation)的一种方式, 由X失活中心 (X-inactivation center, Xic)调控. 在Xic中, X染色体 失活特异转录本(X-inactive specific transcript, Xist)的 表达能引发X染色体失活, 同时也有研究表明多种 ncRNA、非组蛋白等分子也共同参与了XCI的维持和 建立 [37,39,40] .…”