Novel players of x chromosome inactivation: recent insights

Halimeh Rezaei ,1,* Sheyda khalilian,2

1. Division of Genetics, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran, IR Iran
2. Division of Genetics, Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Iran, IR Iran

Abstract

Introduction

To achieve a balanced gene expression dosage between males (xy) and females (xx), mammals have evolved a mechanism to randomly inactivate one of the female x chromosomes. x chromosome inactivation (xci), starts with the upregulation of the long non-coding rna, xist, after silencing the most x-linked genes and acquires some chromatin modifications. although the choice of x chromosome to be silenced is random, this process is highly regulated, but the mechanisms and several of the regulatory factors responsible for the initiation of xci, remain largely unknown. recent technological advances have identified several new key factors that play a significant role in xci. skewed x inactivation can result in expression of the phenotype of x-linked diseases and these similar identifications are important for detecting pathogenic variants in x-linked diseases. in this review, we discuss recent advances that revealed unexpected factors that are responsible for initiation steps of the gene silencing.

Methods

Multiple databases including pubmed, elsevier and scopus were reviewed.

Results

A set of factors and proteins has been identified to be necessary for the initiation of xist-mediated gene silencing. amongst this list of candidate factors, spen (for split-ends) is identified in all studies and proposed to facilitate the xci initiation through binding to the xist rna. wtap (for wilms tumor associated protein), is another protein identified in the experiments and proposed to have a direct role in xist rna methylation and xist-mediated gene silencing by post-transcriptional control. the exploration of these novel key players can provide new insights into xci initiation mechanism.

Conclusion

The recent studies using molecular and genetic approaches, state that xci involves multiple gene-silencing mechanisms. however; the inter-relationships of the factors playing the key role in related pathways, are challenging. hopefully, identification of regulators of xci proposes an opportunity to explore the mechanism of xist-mediated gene silencing as a potential therapeutic strategy to treat x-linked diseases.

Keywords

X chromosome inactivation, xist, gene silencing, x-linked diseases