Molecular Biology of X Chromosome Inactivation

Intense study of the molecular mechanisms of X inactivation revealed cooperation between molecular changes at many levels. Transcriptional inactivation of genes on the inactive X correlates with binding with several modified histones that are associated with inactivation, and loss of modified histones associated with activation. DNA methylation is associated with silencing, and removing methyl groups causes reactivation. The inactive X is held in a very atypical 3D conformation which obliterates the topological domains obvious on the active X and autosomes. A breakthrough was the discovery that the X inactivation centre contained a gene that was transcribed into a long noncoding RNA only on the inactive X; this XIST gene appears to coordinate modification of DNA and of histones, and binding to membranes, nuclear structures and many protein cofactors.