X Chromosome Inactivation and Autoimmunity

Abstract

Autoimmune diseases appear to have multiple contributing factors including genetics, epigenetics, environmental factors, and aging. The predominance of females among patients with autoimmune diseases suggests possible involvement of the X chromosome and X chromosome inactivation. X chromosome inactivation is an epigenetic event resulting in multiple levels of control for modulation of the expression of X-linked genes in normal female cells such that there remains only one active X chromosome in the cell. The extent of this control is unique among the chromosomes and has the potential for problems when regulation is disrupted. Here we discuss the X chromosome inactivation process and how the X chromosome and X chromosome inactivation may be involved in development of autoimmune disorders.

Autoimmune Diseases and Polyamines

“…dosage compensation), one X chromosome in the female cell is inactivated, resulting in an inactive X (Xi, a.k.a. the Barr body) and an active X (Xa) [5]. This process, X chromosome inactivation (XCI), is a major epigenetic event and there are multiple components used for maintaining XCI, including methylation of DNA in gene promoters and methylation of lysine residues in histone H3 [5,77].…”

“…the Barr body) and an active X (Xa) [5]. This process, X chromosome inactivation (XCI), is a major epigenetic event and there are multiple components used for maintaining XCI, including methylation of DNA in gene promoters and methylation of lysine residues in histone H3 [5,77]. The non-coding X Inactivation Specific Transcript (XIST) RNA is the primary factor involved in initiating and spreading the X inactivation state, starting from the X inactivation center (XIC) at Xq13 on the long arm of the X and spreading along contiguous chromatin until most of the Xi is coated with XIST RNA.…”

“…If epigenetic control of SSAT and/ or SMS on the Xi were lost (i.e., loss of dosage compensation), then over-expression could result in increased polyamine synthesis by SMS and recycling by SSAT, wastefully producing polyamines only to then recycle them, in the process needlessly using SAM, thereby hampering methylation [6,82]. The late replication of the Xi relative to other chromosomes, its peripheral location in the nucleus, and its heavy requirement for methylation to maintain the inactive state means that, relative to other chromosomes, the Xi is potentially more vulnerable to decreases in SAM levels that could result in loss of methylation patterns due to cellular stress or aging [5]. Recurrent stresses could lead to accumulation of hypomethylation sites, particularly in vulnerable chromatin (e.g., Xi) with loss of epigenetic control, including loss of dosage compensation of SSAT and/or SMS.…”

“…However, polyamines are elevated in AID [4]. An important role for polyamines in AID has been proposed previously, based on competition between methylation and polyamines for SAM [5,6]. A particularly intriguing aspect of the hypothesis relates to potential loss of epigenetic control of polyamine genes on the X chromosome that leads to an abnormal increase in polyamine synthesis and recycling, taxing SAM levels and creating higher levels of polyamines and reactive moieties from polyamine oxidation.…”

Epigenetics in autoimmune disorders: Highlights of the 10th Sjögren's Syndrome Symposium

“…As a consequence this new drug should reduce the DNA methylation observed in autoimmune diseases by providing more SAM to the cell. The mechanisms leading to SAM-decarboxylase overexpression in autoimmune diseases were also presented and may be related to the over-expression of the putrecine's pathway (by virus and or as a consequence of the Chromosome X demethylation) [29] …”