Abstract
X inactivation represents a complex multi-layer epigenetic mechanism that profoundly modifies chromatin composition and structure of one X chromosome in females. The heterochromatic inactive X chromosome adopts a unique 3D bipartite structure and a location close to the nuclear periphery or the nucleolus. X-linked lncRNA loci and their transcripts play important roles in the recruitment of proteins that catalyze chromatin and DNA modifications for silencing, as well as in the control of chromatin condensation and location of the inactive X chromosome. A subset of genes escapes X inactivation, raising questions about mechanisms that preserve their expression despite being embedded within heterochromatin. Escape gene expression differs between males and females, which can lead to physiological sex differences. We review recent studies that emphasize challenges in understanding the role of lncRNAs in the control of epigenetic modifications, structural features and nuclear positioning of the inactive X chromosome. Second, we highlight new findings about the distribution of genes that escape X inactivation based on single cell studies, and discuss the roles of escape genes in eliciting sex differences in health and disease.
Highlights
Evolution of the mammalian sex chromosomes from a pair of autosomes resulted in the emergence of distinct heteromorphic chromosomes that govern sex determination (Graves, 2016)
X chromosome inactivation (XCI) is characterized by a cascade of molecular events beginning shortly after embryo implantation, and is faithfully maintained throughout somatic cells in an organism, providing a robust model to study epigenetic and structural changes associated with gene silencing (Galupa and Heard, 2018)
This complex process starts with the cis-coating of the future inactive X chromosome (Xi) by the long-noncoding RNA Xist (Borsani et al, 1991; Brockdorff et al, 1991; Brown et al, 1991)
Summary
Evolution of the mammalian sex chromosomes from a pair of autosomes resulted in the emergence of distinct heteromorphic chromosomes that govern sex determination (Graves, 2016). This review focuses first on mechanisms that govern X chromosome structure and nuclear location in relation to XCI, with a specific emphasis on the role of X-linked lncRNAs in these processes.
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