Review of the “X chromosome-nucleolus nexus” hypothesis of autoimmune diseases with an update explaining disruption of the nucleolus

AbstractThe “X chromosome-nucleolus nexus” hypothesis provides a comprehensive explanation of how autoantibodies can develop following cellular stress. The hypothesis connects autoimmune diseases with the impact of environmental factors, such as viruses, through epigenetic disruption. The inactive X chromos ome, a major epigenetic structure in the female cell’s nucleus, is a key component of the hypothesis. The inactive X is vulnerable to disruption due to the following: (1) its heavy requirements for methylation to suppress gene expression, (2) its peripheral location at the nuclear envelope, (3) it s late replication timing, and (4) its frequently observed close association with the nucleolus. The dynamic nucleolus can expand dramatically in response to cellular stress and this could disrupt the neighboring inactive X, particularly during replication, leading to expression from previously supp ressed chromatin. Especially vulnerable at the surface of the inactive X chromosome would be genes and elements from Xp22 to the terminus of the short arm of the X. Expression of these genes and elements could interfere with nucleolar integrity, nucleolar efficiency, and future nucleolar stress resp onse, and even lead to fragmentation of the nucleolus. Ribonucleoprotein complexes assembled in the nucleolus could be left in incomplete states and inappropriate conformations, and/or contain viral components when the nucleolus is disrupted and these abnormal complexes could initiat...
Source: Immunologic Research - Category: Allergy & Immunology Source Type: research