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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

Abnormal expression of XIST and its regulator genes involved in XCI. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female bipolar (BP) patients with mania and psychosis. Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly higher level of XIST RNA expression was observed in the patients than in the controls (t(23) = − 4.23, p = 0.001). (B) Consistent with its negative role, there was a significantly lower level of TSIX expression in the patients (t(23) = 3.43, p < 0.01). (C) Consistent with its positive role, a trend of high expression of FTX was detected in the patients (t(23) = − 2.00, p < 0.1). (D) No difference was observed in JPX expression between the controls and patients (t(23) = − 0.24, ns). (E) A significantly higher level of KDM5C expression (t(23) = − 2.89, p < 0.05) was observed in the patients. (F) There was a trend of high expression in KDM6A (t(23) = − 2.00, p < 0.1) in the patients before correction of multiple comparisons. (***p < 0.001, **p < 0.01, *p < 0.05, # p < 0.1).
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f0005: Abnormal expression of XIST and its regulator genes involved in XCI. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female bipolar (BP) patients with mania and psychosis. Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly higher level of XIST RNA expression was observed in the patients than in the controls (t(23) = − 4.23, p = 0.001). (B) Consistent with its negative role, there was a significantly lower level of TSIX expression in the patients (t(23) = 3.43, p < 0.01). (C) Consistent with its positive role, a trend of high expression of FTX was detected in the patients (t(23) = − 2.00, p < 0.1). (D) No difference was observed in JPX expression between the controls and patients (t(23) = − 0.24, ns). (E) A significantly higher level of KDM5C expression (t(23) = − 2.89, p < 0.05) was observed in the patients. (F) There was a trend of high expression in KDM6A (t(23) = − 2.00, p < 0.1) in the patients before correction of multiple comparisons. (***p < 0.001, **p < 0.01, *p < 0.05, # p < 0.1).

Mentions: Restriction of abnormal protein translation activity to the female patients' lymphoblastoid cells prompted us to investigate potential dysregulation of X chromosome functions. We examined XCI in female lymphoblastoid cells by quantifying expression of XIST, the master gene for XCI (Brown et al., 1992), and other noncoding RNA genes that are involved in the regulation of XIST expression such as TSIX (Migeon et al., 2002), FTX (Chureau et al., 2002), and JPX (Chureau et al., 2002). We found that expression of XIST is significantly higher (p = 0.001) in the female patients than in the female controls (Fig. 1A). Contrary to high XIST expression, TSIX expression is significantly lower (p < 0.01) in the patients' cells (Fig. 1B). We also observed a trend of high expression of FTX (p < 0.1) in the patients (Fig. 1C), but no difference was found in JPX expression (Fig. 1D). Altered expression of XIST and its negative (TSIX) and positive (FTX) regulator genes within XIC indicates a potential alteration in XCI in the lymphoblastoid cells of the female patients.


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)

Abnormal expression of XIST and its regulator genes involved in XCI. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female bipolar (BP) patients with mania and psychosis. Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly higher level of XIST RNA expression was observed in the patients than in the controls (t(23) = − 4.23, p = 0.001). (B) Consistent with its negative role, there was a significantly lower level of TSIX expression in the patients (t(23) = 3.43, p < 0.01). (C) Consistent with its positive role, a trend of high expression of FTX was detected in the patients (t(23) = − 2.00, p < 0.1). (D) No difference was observed in JPX expression between the controls and patients (t(23) = − 0.24, ns). (E) A significantly higher level of KDM5C expression (t(23) = − 2.89, p < 0.05) was observed in the patients. (F) There was a trend of high expression in KDM6A (t(23) = − 2.00, p < 0.1) in the patients before correction of multiple comparisons. (***p < 0.001, **p < 0.01, *p < 0.05, # p < 0.1).
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f0005: Abnormal expression of XIST and its regulator genes involved in XCI. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female bipolar (BP) patients with mania and psychosis. Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly higher level of XIST RNA expression was observed in the patients than in the controls (t(23) = − 4.23, p = 0.001). (B) Consistent with its negative role, there was a significantly lower level of TSIX expression in the patients (t(23) = 3.43, p < 0.01). (C) Consistent with its positive role, a trend of high expression of FTX was detected in the patients (t(23) = − 2.00, p < 0.1). (D) No difference was observed in JPX expression between the controls and patients (t(23) = − 0.24, ns). (E) A significantly higher level of KDM5C expression (t(23) = − 2.89, p < 0.05) was observed in the patients. (F) There was a trend of high expression in KDM6A (t(23) = − 2.00, p < 0.1) in the patients before correction of multiple comparisons. (***p < 0.001, **p < 0.01, *p < 0.05, # p < 0.1).
Mentions: Restriction of abnormal protein translation activity to the female patients' lymphoblastoid cells prompted us to investigate potential dysregulation of X chromosome functions. We examined XCI in female lymphoblastoid cells by quantifying expression of XIST, the master gene for XCI (Brown et al., 1992), and other noncoding RNA genes that are involved in the regulation of XIST expression such as TSIX (Migeon et al., 2002), FTX (Chureau et al., 2002), and JPX (Chureau et al., 2002). We found that expression of XIST is significantly higher (p = 0.001) in the female patients than in the female controls (Fig. 1A). Contrary to high XIST expression, TSIX expression is significantly lower (p < 0.01) in the patients' cells (Fig. 1B). We also observed a trend of high expression of FTX (p < 0.1) in the patients (Fig. 1C), but no difference was found in JPX expression (Fig. 1D). Altered expression of XIST and its negative (TSIX) and positive (FTX) regulator genes within XIC indicates a potential alteration in XCI in the lymphoblastoid cells of the female patients.

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