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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

Variation of protein translation activity in patients' lymphoblastoid cells. (A) Protein translation activity was measured in individual lymphoblastoid cell lines using SUnSET. Sample loading was shown by β-actin protein expression after stripping the membrane. C1–C26: healthy European Caucasian controls; B1–B28: European Caucasian bipolar patients with mania and psychosis. (B) SUnSET intensity of individual samples was normalized against β-actin. To avoid differential overall intensity between the gels, the intensity of each sample is presented as a percentage of the average intensity of all samples from the same gel. A significantly larger variation of protein translation activity was observed in the patients than in the controls (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis. (C) Comparison of intracellular puromycin concentrations. Two cell lines (B25 and B27) with a marked difference in SUnSET activity were selected. Equal amounts of puromycin-labeled protein were loaded on each lane. B25 and B27 cell lysates were used to block interaction between membrane-bound puromycin-labeled proteins and anti-puromycin antibodies in the Western blot blocking solution. Western blot signal was gradually decreased after adding an increasing amount of cell lysate to the blocking solution. There was no difference between the blocking activities of B25 and B27 cell lysate, indicating that there was a comparable concentration of intracellular puromycin between the two cell lines. (D) There was no correlation between protein translation activity (SUnSET) and individuals' age. Each dot represents a human subject. (E) SUnSET data were analyzed according to gender. There was no difference between male controls and male patients. A significantly larger variation of protein translation activity was observed in female patients (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis.
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f0035: Variation of protein translation activity in patients' lymphoblastoid cells. (A) Protein translation activity was measured in individual lymphoblastoid cell lines using SUnSET. Sample loading was shown by β-actin protein expression after stripping the membrane. C1–C26: healthy European Caucasian controls; B1–B28: European Caucasian bipolar patients with mania and psychosis. (B) SUnSET intensity of individual samples was normalized against β-actin. To avoid differential overall intensity between the gels, the intensity of each sample is presented as a percentage of the average intensity of all samples from the same gel. A significantly larger variation of protein translation activity was observed in the patients than in the controls (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis. (C) Comparison of intracellular puromycin concentrations. Two cell lines (B25 and B27) with a marked difference in SUnSET activity were selected. Equal amounts of puromycin-labeled protein were loaded on each lane. B25 and B27 cell lysates were used to block interaction between membrane-bound puromycin-labeled proteins and anti-puromycin antibodies in the Western blot blocking solution. Western blot signal was gradually decreased after adding an increasing amount of cell lysate to the blocking solution. There was no difference between the blocking activities of B25 and B27 cell lysate, indicating that there was a comparable concentration of intracellular puromycin between the two cell lines. (D) There was no correlation between protein translation activity (SUnSET) and individuals' age. Each dot represents a human subject. (E) SUnSET data were analyzed according to gender. There was no difference between male controls and male patients. A significantly larger variation of protein translation activity was observed in female patients (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis.

Mentions: To measure protein translation activity, lymphoblastoid cells were first serum-starved for 8 h to synchronize cell growth before re-stimulated with a normal concentration of serum. Protein translation activity was measured 8 h after serum re-stimulation using the SUnSET (surface sensing of translation) method (Ji et al., 2014, Schmidt et al., 2009). After analyzing 26 healthy controls and 28 bipolar patients with severe mania and psychosis, we found a significantly larger variation of protein translation activity in the patients' lymphoblastoid cell lines (Fig. S1A and B). The different SUnSET intensities between cell lines came from differential activities of protein synthesis rather than differential uptake of puromycin (Fig. S1C). A high correlation of SUnSET intensities between the synchronized cells and asynchronized proliferating cells was observed (data not shown). No correlation was found between individuals' age and protein translation activity (Fig. S1D). When the SUnSET data were sub-grouped according to gender, however, we found that all variations in protein translation activity came from the female patients (Fig. S1E).


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)

Variation of protein translation activity in patients' lymphoblastoid cells. (A) Protein translation activity was measured in individual lymphoblastoid cell lines using SUnSET. Sample loading was shown by β-actin protein expression after stripping the membrane. C1–C26: healthy European Caucasian controls; B1–B28: European Caucasian bipolar patients with mania and psychosis. (B) SUnSET intensity of individual samples was normalized against β-actin. To avoid differential overall intensity between the gels, the intensity of each sample is presented as a percentage of the average intensity of all samples from the same gel. A significantly larger variation of protein translation activity was observed in the patients than in the controls (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis. (C) Comparison of intracellular puromycin concentrations. Two cell lines (B25 and B27) with a marked difference in SUnSET activity were selected. Equal amounts of puromycin-labeled protein were loaded on each lane. B25 and B27 cell lysates were used to block interaction between membrane-bound puromycin-labeled proteins and anti-puromycin antibodies in the Western blot blocking solution. Western blot signal was gradually decreased after adding an increasing amount of cell lysate to the blocking solution. There was no difference between the blocking activities of B25 and B27 cell lysate, indicating that there was a comparable concentration of intracellular puromycin between the two cell lines. (D) There was no correlation between protein translation activity (SUnSET) and individuals' age. Each dot represents a human subject. (E) SUnSET data were analyzed according to gender. There was no difference between male controls and male patients. A significantly larger variation of protein translation activity was observed in female patients (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
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f0035: Variation of protein translation activity in patients' lymphoblastoid cells. (A) Protein translation activity was measured in individual lymphoblastoid cell lines using SUnSET. Sample loading was shown by β-actin protein expression after stripping the membrane. C1–C26: healthy European Caucasian controls; B1–B28: European Caucasian bipolar patients with mania and psychosis. (B) SUnSET intensity of individual samples was normalized against β-actin. To avoid differential overall intensity between the gels, the intensity of each sample is presented as a percentage of the average intensity of all samples from the same gel. A significantly larger variation of protein translation activity was observed in the patients than in the controls (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis. (C) Comparison of intracellular puromycin concentrations. Two cell lines (B25 and B27) with a marked difference in SUnSET activity were selected. Equal amounts of puromycin-labeled protein were loaded on each lane. B25 and B27 cell lysates were used to block interaction between membrane-bound puromycin-labeled proteins and anti-puromycin antibodies in the Western blot blocking solution. Western blot signal was gradually decreased after adding an increasing amount of cell lysate to the blocking solution. There was no difference between the blocking activities of B25 and B27 cell lysate, indicating that there was a comparable concentration of intracellular puromycin between the two cell lines. (D) There was no correlation between protein translation activity (SUnSET) and individuals' age. Each dot represents a human subject. (E) SUnSET data were analyzed according to gender. There was no difference between male controls and male patients. A significantly larger variation of protein translation activity was observed in female patients (p < 0.01, F-test). Each dot represents a human subject (black = healthy controls; red = patients). CTRL: controls; BP: bipolar patients with mania and psychosis.
Mentions: To measure protein translation activity, lymphoblastoid cells were first serum-starved for 8 h to synchronize cell growth before re-stimulated with a normal concentration of serum. Protein translation activity was measured 8 h after serum re-stimulation using the SUnSET (surface sensing of translation) method (Ji et al., 2014, Schmidt et al., 2009). After analyzing 26 healthy controls and 28 bipolar patients with severe mania and psychosis, we found a significantly larger variation of protein translation activity in the patients' lymphoblastoid cell lines (Fig. S1A and B). The different SUnSET intensities between cell lines came from differential activities of protein synthesis rather than differential uptake of puromycin (Fig. S1C). A high correlation of SUnSET intensities between the synchronized cells and asynchronized proliferating cells was observed (data not shown). No correlation was found between individuals' age and protein translation activity (Fig. S1D). When the SUnSET data were sub-grouped according to gender, however, we found that all variations in protein translation activity came from the female patients (Fig. S1E).

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