X Inactivation and Escape: Epigenetic and Structural Features

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.

Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

“…Due to the imbalance of X chromosome between females (XX) and males (XY), regulation of X-linked gene dosage is strictly necessary. Abnormal increase in X-linked gene expression due to the presence of the extra X chromosome in females leads to developmental dysfunction [ 13 ]. Therefore, in female mammals, one of the two X chromosomes is randomly inactivated, in the early embryo, to balance the dosage of gene expression between the sexes.…”

“…Therefore, in female mammals, one of the two X chromosomes is randomly inactivated, in the early embryo, to balance the dosage of gene expression between the sexes. The process of X chromosome inactivation (XCI) results in cellular mosaicism ( Figure 1 ), where about half of the cells in a tissue express genes from the maternal X chromosome and the other half from the paternal X chromosome [ 13 ]. However, the pseudo-autosomal regions (PAR) of the X chromosome, PAR1 and PAR2, do not undergo XCI ( Figure 2 ).…”

Sex Differences in Cancer Cachexia

“…Approximately 15–30% of human X chromosome-linked genes escape inactivation (XCI), a mechanism that silences a randomly chosen X chromosome in females to ensure X-linked gene dosage compensation between females (XX) and males (XY). Because some X-linked miRNAs are intronic in the protein-coding genes [ 91 ] and some of the host protein-coding genes have been shown to escape X chromosome inactivation, certain miRNAs are likely subject to escaping XCI [ 91 – 94 ], leading to imbalanced or enhanced expression between sexes and to a sex-specific response. Of course, this novel mechanism we propose requires validation in the future by more studies profiling the expression of miRNAs in both males and females with cancer cachexia and analyzing the results by sex.…”

Dernières nouvelles du chromosome X

“…Cependant, le statut d'inactivation du X n'ayant pas été étudié en détail dans ces souris mutantes, la question de l'action de XIST sur le maintien de l'état inactif du chromosome X reste ouverte. [39]. L'approfondissement de notre connaissance de la régulation et de la stabilité de l'inactivation du X chez l'adulte pourrait donc révéler de nouveaux mécanismes à l'origine de ces diverses maladies (cancer, autisme, épilepsie et maladies du système immunitaire) et, idéalement, nous permettre d'identifier des biomarqueurs et de nouvelles cibles thérapeutiques spécifiques.…”