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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

No effect of CLZ and VPA treatment on expression of XIST, TSIX, KDM5C and KDM6A genes. Clozapine (CLZ) and valproic acid (VPA) were dissolved in methanol. Both control and patient lymphoblastoid cells were cultured in the presence of CLZ and VPA at the final concentration of 0.5 μg/ml and 50 μg/ml respectively. After 72 h incubation, CLZ and VPA were removed. Gene expression analysis was conducted in cells after 4 day recovery in normal culture medium. There was no effect of drug treatment on expression of XIST (A), TSIX (B), KDM5C (C), and KDM6A (D) genes. Error bar: SEM.
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f0045: No effect of CLZ and VPA treatment on expression of XIST, TSIX, KDM5C and KDM6A genes. Clozapine (CLZ) and valproic acid (VPA) were dissolved in methanol. Both control and patient lymphoblastoid cells were cultured in the presence of CLZ and VPA at the final concentration of 0.5 μg/ml and 50 μg/ml respectively. After 72 h incubation, CLZ and VPA were removed. Gene expression analysis was conducted in cells after 4 day recovery in normal culture medium. There was no effect of drug treatment on expression of XIST (A), TSIX (B), KDM5C (C), and KDM6A (D) genes. Error bar: SEM.

Mentions: Altered expression of XIST, TSIX, KDM5C and KDM6A genes in patients' lymphoblastoid cells is unlikely caused by any medication history of the patients because prior treatment of lymphoblastoid cells with both antipsychotics clozapine (CLZ) and mood stabilizer valproic acid (VPA) has no effect on expression of any of these genes (Fig. S3A, B, C, D). Additionally, expression of KDM5C and KDM6A genes was not different in the lymphoblastoid cells of male patients from the healthy male controls (Fig. S4), supporting that patients' medication history has no effect on expression of X-linked genes in their lymphoblastoid cells. Neither XIST nor KDM5C expression is affected by age (Fig. S5A, B). There is no correlation between XIST expression and protein translation activity (SUnSET) (Fig. S5C). A weak correlation between KDM5C expression and SUnSET intensity was observed, but statistically insignificant (Fig. S5D). It is possible that other autosomal genes that vary between individuals may also be involved in the regulation of protein translation activity.


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)

No effect of CLZ and VPA treatment on expression of XIST, TSIX, KDM5C and KDM6A genes. Clozapine (CLZ) and valproic acid (VPA) were dissolved in methanol. Both control and patient lymphoblastoid cells were cultured in the presence of CLZ and VPA at the final concentration of 0.5 μg/ml and 50 μg/ml respectively. After 72 h incubation, CLZ and VPA were removed. Gene expression analysis was conducted in cells after 4 day recovery in normal culture medium. There was no effect of drug treatment on expression of XIST (A), TSIX (B), KDM5C (C), and KDM6A (D) genes. Error bar: SEM.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0045: No effect of CLZ and VPA treatment on expression of XIST, TSIX, KDM5C and KDM6A genes. Clozapine (CLZ) and valproic acid (VPA) were dissolved in methanol. Both control and patient lymphoblastoid cells were cultured in the presence of CLZ and VPA at the final concentration of 0.5 μg/ml and 50 μg/ml respectively. After 72 h incubation, CLZ and VPA were removed. Gene expression analysis was conducted in cells after 4 day recovery in normal culture medium. There was no effect of drug treatment on expression of XIST (A), TSIX (B), KDM5C (C), and KDM6A (D) genes. Error bar: SEM.
Mentions: Altered expression of XIST, TSIX, KDM5C and KDM6A genes in patients' lymphoblastoid cells is unlikely caused by any medication history of the patients because prior treatment of lymphoblastoid cells with both antipsychotics clozapine (CLZ) and mood stabilizer valproic acid (VPA) has no effect on expression of any of these genes (Fig. S3A, B, C, D). Additionally, expression of KDM5C and KDM6A genes was not different in the lymphoblastoid cells of male patients from the healthy male controls (Fig. S4), supporting that patients' medication history has no effect on expression of X-linked genes in their lymphoblastoid cells. Neither XIST nor KDM5C expression is affected by age (Fig. S5A, B). There is no correlation between XIST expression and protein translation activity (SUnSET) (Fig. S5C). A weak correlation between KDM5C expression and SUnSET intensity was observed, but statistically insignificant (Fig. S5D). It is possible that other autosomal genes that vary between individuals may also be involved in the regulation of protein translation activity.

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