The Role of Long Non-coding RNAs in Human Imprinting Disorders: Prospective Therapeutic Targets.

Qing Ma,Manyin Wu,Tingxuan Wang,Liuyi Yang,Jianjian Li

doi:10.3389/fcell.2021.730014

Abstract

Genomic imprinting is a term used for an intergenerational epigenetic inheritance and involves a subset of genes expressed in a parent-of-origin-dependent way. Imprinted genes are expressed preferentially from either the paternally or maternally inherited allele. Long non-coding RNAs play essential roles in regulating this allele-specific expression. In several well-studied imprinting clusters, long non-coding RNAs have been found to be essential in regulating temporal- and spatial-specific establishment and maintenance of imprinting patterns. Furthermore, recent insights into the epigenetic pathological mechanisms underlying human genomic imprinting disorders suggest that allele-specific expressed imprinted long non-coding RNAs serve as an upstream regulator of the expression of other protein-coding or non-coding imprinted genes in the same cluster. Aberrantly expressed long non-coding RNAs result in bi-allelic expression or silencing of neighboring imprinted genes. Here, we review the emerging roles of long non-coding RNAs in regulating the expression of imprinted genes, especially in human imprinting disorders, and discuss three strategies targeting the central long non-coding RNA UBE3A-ATS for the purpose of developing therapies for the imprinting disorders Prader–Willi syndrome and Angelman syndrome. In summary, a better understanding of long non-coding RNA-related mechanisms is key to the development of potential therapeutic targets for human imprinting disorders.

Highlights

In diploid organisms, most genes are transcribed in an unbiased fashion from both alleles
After imprinting patterns become established in mature germlines, genomic imprinting in an individual is maintained until genome-wide erasure of epigenetic modification occurs in gamete precursors
Several imprinting gene clusters have been discovered and studied since the middle of the last century. These studies have shown that long non-coding RNAs (lncRNAs) play crucial roles in regulating imprinted gene clusters and individual imprinted genes related to human health and diseases

Summary

Introduction

Most genes are transcribed in an unbiased fashion from both alleles. On the paternal allele of imprinted human PWS/AS locus, the unmethylated PWS-ICR is the region upstream to a proteincoding gene SNRPN and a lncRNA SNHG14 (small nucleolar RNA host gene 14) (Sutcliffe et al, 1994; Buiting et al, 1995; Rougeulle et al, 1997; Runte et al, 2001; Vitali et al, 2010; Chamberlain, 2013; Stanurova et al, 2018; Figure 4A).

Results

Conclusion