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    • br Discussion Our studies suggest that

    2018-11-13


    Discussion Our studies suggest that over-expression of both XIST and KDM5C genes may serve as a biological marker for diagnosis of bipolar disorder with mania and psychosis or recurrent major depression in females. In 60 lymphoblastoid cell lines established from randomly collected female patients from the general population, about 30% to 60% of the patients can be diagnosed by these markers using different stringency. Not all female patients displayed over-expression of XIST and/or KDM5C genes, suggesting heterogeneity of genetic etiologies in the general population of female patients. Most of the female patients used in our studies have a family history of mental disorders and display severe psychiatric symptoms. Therefore, our studies may over-estimate the prevalence of abnormal XIST and KDM5C expression in the general population of female psychiatric patients without family history and/or with milder psychiatric symptoms. The levels of XIST and KDM5C expression are stable between different passages of lymphoblastoid cells. Their expression is unaffected by patients\' ages when the blood was drawn for establishment of lymphoblastoid cell lines. Consistent with our studies on humans, mouse Xist expression maintains the same high level of expression across development (Buzin et al., 1994) and between different adult tissues (Kay et al., 1993; Ma and Strauss, 2005). We propose that XIST expression could be a stable trait that associates with the state of X chromosomes in female somatic CB-5083 since establishment of XCI. Given that psychiatric symptoms mostly develop in late adolescence, it may be feasible to measure XIST and KDM5C expression in the lymphocytes from girls at childhood or early adolescence to predict the risk of developing major psychiatric disorders in young adulthood. Such studies merit further investigation in the future, as early diagnosis can greatly help early intervention as demonstrated in autism (Rogers et al., 2014). XIST is a unique gene. It encodes a 19kb long noncoding RNA and serves as the master gene in both initiation (Kay et al., 1993; Penny et al., 1996; Plath et al., 2002) and maintenance (Yildirim et al., 2013) of X chromosome inactivation (XCI). Mouse Tsix, Ftx, and Jpx genes, localized in X chromosome inactivation center (XIC), have been demonstrated to regulate expression of Xist during XCI initiation (Lee et al., 1999; Chureau et al., 2011; Tian et al., 2010). In the lymphoblastoid cell lines, significant down-regulation of TSIX (a negative regulator of XIST expression) and a trend of high level of FTX (a positive regulator of XIST expression) were observed in the patients with mania and psychosis. However, we failed to detect significant differences in their expression in the patients with recurrent major depression. It is unclear what roles these negative and positive noncoding RNAs play in regulation of XIST expression in the lymphoblastoid cells. In addition, epigenetic modifications of XIST and KDM5C loci are also altered, which accompany over-expression of both genes in patients\' lymphoblastoid cell lines. Taken together, all of these data support aberrant regulation and expression of XIST and some other X-linked genes in the patients\' lymphoblastoid cells. We suggest that subtle XCI deficiency may occur in the patients\' lymphoblastoid cells to cause over-expression of X-linked escapee genes KDM5C and KDM6A. Over-expression of XIST may be a compensatory response to XCI deficiency. Such a subtle deficiency appears to be insufficient to cause over-expression of most X-linked genes since we did not observe consistent up-regulation of PGK1, G6PD and HPRT1 genes in patients\' lymphoblastoid cell lines. However, over-expression of XIST may alter epigenetic state of inactive X chromosome via recruiting excessive XIST-dependent protein complexes. Therefore, we cannot rule out potential active roles of XIST over-expression in regulation of XCI, although the exact mechanisms remain to be investigated. There is a robust correlation between XIST and KDM5C expression in patients\' lymphoblastoid cell lines. However, we did not observe such a correlation in the cingulate cortex of postmortem brains. Given that X-linked escapee genes display tissue-specific variation in degree of escape (Berletch et al., 2015; Sheardown et al., 1996), the correlation between XIST and KDM5C expression may be cell-specific. Additionally, other confounding factors such as tissue heterogeneity in the postmortem brains may disrupt such a correlation (if there is any). Due to lack of allele-specific polymorphisms of XIST RNA in our samples, we do not know whether XIST over-expression comes exclusively from the inactive X chromosome in patients\' lymphoblastoid cell lines. RNA fluorescent in situ hybridization (FISH) experiments on patients\' lymphoblastoid cells may be conducted in the future to clarify the localization of XIST over-expression.