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Over-expression of XIST, the Master Gene for X Chromosome Inactivation, in Females With Major Affective Disorders.

Ji B, Higa KK, Kelsoe JR, Zhou X - EBioMedicine (2015)

Bottom Line: Classic genetic studies found that an extra X chromosome frequently causes psychiatric symptoms in patients with either Klinefelter syndrome (XXY) or Triple X syndrome (XXX).We found that the XIST gene, a master in control of X chromosome inactivation (XCI), is significantly over-expressed (p = 1 × 10(- 7), corrected after multiple comparisons) in the lymphoblastoid cells of female patients with either bipolar disorder or major depression.We found that XIST and KDM5C gene expression may be used as a biological marker for diagnosis of major affective disorders in a significantly large subset of female patients from the general population.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

ABSTRACT

Background: Psychiatric disorders are common mental disorders without a pathological biomarker. Classic genetic studies found that an extra X chromosome frequently causes psychiatric symptoms in patients with either Klinefelter syndrome (XXY) or Triple X syndrome (XXX). Over-dosage of some X-linked escapee genes was suggested to cause psychiatric disorders. However, relevance of these rare genetic diseases to the pathogenesis of psychiatric disorders in the general population of psychiatric patients is unknown.

Methods: XIST and several X-linked genes were studied in 36 lymphoblastoid cell lines from healthy females and 60 lymphoblastoid cell lines from female patients with either bipolar disorder or recurrent major depression. XIST and KDM5C expression was also quantified in 48 RNA samples from postmortem human brains of healthy female controls and female psychiatric patients.

Findings: We found that the XIST gene, a master in control of X chromosome inactivation (XCI), is significantly over-expressed (p = 1 × 10(- 7), corrected after multiple comparisons) in the lymphoblastoid cells of female patients with either bipolar disorder or major depression. The X-linked escapee gene KDM5C also displays significant up-regulation (p = 5.3 × 10(- 7), corrected after multiple comparisons) in the patients' cells. Expression of XIST and KDM5C is highly correlated (Pearson's coefficient, r = 0.78, p = 1.3 × 10(- 13)). Studies on human postmortem brains supported over-expression of the XIST gene in female psychiatric patients.

Interpretations: We propose that over-expression of XIST may cause or result from subtle alteration of XCI, which up-regulates the expression of some X-linked escapee genes including KDM5C. Over-expression of X-linked genes could be a common mechanism for the development of psychiatric disorders between patients with those rare genetic diseases and the general population of female psychiatric patients with XIST over-expression. Our studies suggest that XIST and KDM5C expression could be used as a biological marker for diagnosis of psychiatric disorders in a significantly large subset of female patients.

Research in context: Due to lack of biological markers, diagnosis and treatment of psychiatric disorders are subjective. There is utmost urgency to identify biomarkers for clinics, research, and drug development. We found that XIST and KDM5C gene expression may be used as a biological marker for diagnosis of major affective disorders in a significantly large subset of female patients from the general population. Our studies show that over-expression of XIST and some X-linked escapee genes may be a common mechanism for development of psychiatric disorders between the patients with rare genetic diseases (XXY or XXX) and the general population of female psychiatric patients.

No MeSH data available.


Related in: MedlinePlus

Expression of X-linked genes in patients' lymphoblastoid cell lines. Each dot represents a human subject (black = healthy controls; red = patients). A trend of high expression in PGK1 (A)(t(23) = − 1.84, p < 0.1), G6PD (B)(t(23) = − 1.89, p < 0.1) in the patients before correction of multiple comparisons. There was no significant difference in HPRT1 (C)(t(23) = − 1.62, ns) and RPS4X (D)(t(23) = − 0.57, ns) expression between the controls and the patients. (E) When GAPDH was used as the reference control, a significant over-expression of XIST was also observed (t(23) = − 2.61, p = 0.016).
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f0040: Expression of X-linked genes in patients' lymphoblastoid cell lines. Each dot represents a human subject (black = healthy controls; red = patients). A trend of high expression in PGK1 (A)(t(23) = − 1.84, p < 0.1), G6PD (B)(t(23) = − 1.89, p < 0.1) in the patients before correction of multiple comparisons. There was no significant difference in HPRT1 (C)(t(23) = − 1.62, ns) and RPS4X (D)(t(23) = − 0.57, ns) expression between the controls and the patients. (E) When GAPDH was used as the reference control, a significant over-expression of XIST was also observed (t(23) = − 2.61, p = 0.016).

Mentions: To investigate whether other X-linked genes beyond XIC are affected, we randomly selected a few genes that are either completely inactivated by or escapees from XCI. PGK1, G6PD and HPRT1 genes are known to be inactivated by XCI, and KDM5C, KDM6A and RPS4X genes are the well-established escapees from XCI in human lymphoblastoid cells (Johnston et al., 2008). We found that expression of KDM5C is significantly higher (p < 0.05) in the female patients than in the female controls (Fig. 1E). A trend of high expression (p < 0.1) of KDM6A (Fig. 1F), PGK1 and G6PD genes (Fig. S2A and B) was observed in the patients' cells before correction of multiple comparisons. No difference was found in expression of either HPRT1 or RPS4X gene between the patients and the controls (Fig. S2C and D). Expression of all these genes was quantified with β-actin as the reference control. Using GAPDH as a different reference control, we confirmed over-expression of XIST in the patients' cells (Fig. S2E). Since GAPDH expression is likely more sensitive to cell culture conditions, we continued to use β-actin expression as the reference control for all subsequent studies.


Over-expression of XIST, the Master Gene for X Chromosome Inactivation, in Females With Major Affective Disorders.

Ji B, Higa KK, Kelsoe JR, Zhou X - EBioMedicine (2015)

Expression of X-linked genes in patients' lymphoblastoid cell lines. Each dot represents a human subject (black = healthy controls; red = patients). A trend of high expression in PGK1 (A)(t(23) = − 1.84, p < 0.1), G6PD (B)(t(23) = − 1.89, p < 0.1) in the patients before correction of multiple comparisons. There was no significant difference in HPRT1 (C)(t(23) = − 1.62, ns) and RPS4X (D)(t(23) = − 0.57, ns) expression between the controls and the patients. (E) When GAPDH was used as the reference control, a significant over-expression of XIST was also observed (t(23) = − 2.61, p = 0.016).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563114&req=5

f0040: Expression of X-linked genes in patients' lymphoblastoid cell lines. Each dot represents a human subject (black = healthy controls; red = patients). A trend of high expression in PGK1 (A)(t(23) = − 1.84, p < 0.1), G6PD (B)(t(23) = − 1.89, p < 0.1) in the patients before correction of multiple comparisons. There was no significant difference in HPRT1 (C)(t(23) = − 1.62, ns) and RPS4X (D)(t(23) = − 0.57, ns) expression between the controls and the patients. (E) When GAPDH was used as the reference control, a significant over-expression of XIST was also observed (t(23) = − 2.61, p = 0.016).
Mentions: To investigate whether other X-linked genes beyond XIC are affected, we randomly selected a few genes that are either completely inactivated by or escapees from XCI. PGK1, G6PD and HPRT1 genes are known to be inactivated by XCI, and KDM5C, KDM6A and RPS4X genes are the well-established escapees from XCI in human lymphoblastoid cells (Johnston et al., 2008). We found that expression of KDM5C is significantly higher (p < 0.05) in the female patients than in the female controls (Fig. 1E). A trend of high expression (p < 0.1) of KDM6A (Fig. 1F), PGK1 and G6PD genes (Fig. S2A and B) was observed in the patients' cells before correction of multiple comparisons. No difference was found in expression of either HPRT1 or RPS4X gene between the patients and the controls (Fig. S2C and D). Expression of all these genes was quantified with β-actin as the reference control. Using GAPDH as a different reference control, we confirmed over-expression of XIST in the patients' cells (Fig. S2E). Since GAPDH expression is likely more sensitive to cell culture conditions, we continued to use β-actin expression as the reference control for all subsequent studies.

Bottom Line: Classic genetic studies found that an extra X chromosome frequently causes psychiatric symptoms in patients with either Klinefelter syndrome (XXY) or Triple X syndrome (XXX).We found that the XIST gene, a master in control of X chromosome inactivation (XCI), is significantly over-expressed (p = 1 × 10(- 7), corrected after multiple comparisons) in the lymphoblastoid cells of female patients with either bipolar disorder or major depression.We found that XIST and KDM5C gene expression may be used as a biological marker for diagnosis of major affective disorders in a significantly large subset of female patients from the general population.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

ABSTRACT

Background: Psychiatric disorders are common mental disorders without a pathological biomarker. Classic genetic studies found that an extra X chromosome frequently causes psychiatric symptoms in patients with either Klinefelter syndrome (XXY) or Triple X syndrome (XXX). Over-dosage of some X-linked escapee genes was suggested to cause psychiatric disorders. However, relevance of these rare genetic diseases to the pathogenesis of psychiatric disorders in the general population of psychiatric patients is unknown.

Methods: XIST and several X-linked genes were studied in 36 lymphoblastoid cell lines from healthy females and 60 lymphoblastoid cell lines from female patients with either bipolar disorder or recurrent major depression. XIST and KDM5C expression was also quantified in 48 RNA samples from postmortem human brains of healthy female controls and female psychiatric patients.

Findings: We found that the XIST gene, a master in control of X chromosome inactivation (XCI), is significantly over-expressed (p = 1 × 10(- 7), corrected after multiple comparisons) in the lymphoblastoid cells of female patients with either bipolar disorder or major depression. The X-linked escapee gene KDM5C also displays significant up-regulation (p = 5.3 × 10(- 7), corrected after multiple comparisons) in the patients' cells. Expression of XIST and KDM5C is highly correlated (Pearson's coefficient, r = 0.78, p = 1.3 × 10(- 13)). Studies on human postmortem brains supported over-expression of the XIST gene in female psychiatric patients.

Interpretations: We propose that over-expression of XIST may cause or result from subtle alteration of XCI, which up-regulates the expression of some X-linked escapee genes including KDM5C. Over-expression of X-linked genes could be a common mechanism for the development of psychiatric disorders between patients with those rare genetic diseases and the general population of female psychiatric patients with XIST over-expression. Our studies suggest that XIST and KDM5C expression could be used as a biological marker for diagnosis of psychiatric disorders in a significantly large subset of female patients.

Research in context: Due to lack of biological markers, diagnosis and treatment of psychiatric disorders are subjective. There is utmost urgency to identify biomarkers for clinics, research, and drug development. We found that XIST and KDM5C gene expression may be used as a biological marker for diagnosis of major affective disorders in a significantly large subset of female patients from the general population. Our studies show that over-expression of XIST and some X-linked escapee genes may be a common mechanism for development of psychiatric disorders between the patients with rare genetic diseases (XXY or XXX) and the general population of female psychiatric patients.

No MeSH data available.


Related in: MedlinePlus