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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

XIST and KDM5C expression across passages and alteration of epigenetic modifications in the patients. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR). XIST (A) and KDM5C (B) gene expression was examined in the first batch of lymphoblastoid cells (XIST-1 and KDM5C-1). After more than a month of continuous cell culture, the same set of genes was examined again in the second batch of the same cell lines with different cell passages (XIST-2 and KDM5C-2). A high correlation of XIST (Pearson's coefficient, r = 0.88, p = 2.6 × 10− 8) and KDM5C (Pearson's coefficient, r = 0.6, p = 0.0028) expression was observed between the two batches of cells with different passages. (C) Western blot analyses of KDM5C protein expression in the lymphoblastoid cells of female patients with recurrent major depression. A single band at 180 kD, the calculated size of human KDM5C protein, was detected. C: controls; D: recurrent major depression. β-actin was used as an internal control for normalization. (D) Consistent with increased mRNA expression, significantly higher KDM5C protein expression was found in the patients (t(22) = − 2.85, p < 0.01). (E) Lymphoblastoid cell lines from 4 female controls (black) and 4 female patients (red) with either recurrent major depression or mania and psychosis were selected for chromatin immunoprecipitation experiments. Six sites, separated by ~ 1 kb (except a 2 kb between 1 and 2) around the promoter of XIST gene, were examined by ChIP-QPCR. Multiple comparisons of Student's t-tests were corrected with FDR. Significantly more H3K27me3 was observed in the patients' lymphoblastoid cells at XIST (1) (t(6) = − 3.83, p < 0.05) and XIST (3) (t(6) = − 3.2, p < 0.05). A trend of more H3K27me3 at XIST (4) (t(6) = − 2.7, p < 0.1) was also observed. (F) Two sites around the promoter of KDM5C gene were also examined by CHIP-QPCR. H3K27me3 is significantly more enriched at KDM5C (1) (t(6) = − 3.39, p < 0.05) in female patients' lymphoblastoid cells.
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f0025: XIST and KDM5C expression across passages and alteration of epigenetic modifications in the patients. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR). XIST (A) and KDM5C (B) gene expression was examined in the first batch of lymphoblastoid cells (XIST-1 and KDM5C-1). After more than a month of continuous cell culture, the same set of genes was examined again in the second batch of the same cell lines with different cell passages (XIST-2 and KDM5C-2). A high correlation of XIST (Pearson's coefficient, r = 0.88, p = 2.6 × 10− 8) and KDM5C (Pearson's coefficient, r = 0.6, p = 0.0028) expression was observed between the two batches of cells with different passages. (C) Western blot analyses of KDM5C protein expression in the lymphoblastoid cells of female patients with recurrent major depression. A single band at 180 kD, the calculated size of human KDM5C protein, was detected. C: controls; D: recurrent major depression. β-actin was used as an internal control for normalization. (D) Consistent with increased mRNA expression, significantly higher KDM5C protein expression was found in the patients (t(22) = − 2.85, p < 0.01). (E) Lymphoblastoid cell lines from 4 female controls (black) and 4 female patients (red) with either recurrent major depression or mania and psychosis were selected for chromatin immunoprecipitation experiments. Six sites, separated by ~ 1 kb (except a 2 kb between 1 and 2) around the promoter of XIST gene, were examined by ChIP-QPCR. Multiple comparisons of Student's t-tests were corrected with FDR. Significantly more H3K27me3 was observed in the patients' lymphoblastoid cells at XIST (1) (t(6) = − 3.83, p < 0.05) and XIST (3) (t(6) = − 3.2, p < 0.05). A trend of more H3K27me3 at XIST (4) (t(6) = − 2.7, p < 0.1) was also observed. (F) Two sites around the promoter of KDM5C gene were also examined by CHIP-QPCR. H3K27me3 is significantly more enriched at KDM5C (1) (t(6) = − 3.39, p < 0.05) in female patients' lymphoblastoid cells.

Mentions: We investigated whether cell passages may alter expression of XIST, KDM5C, and KDM6A genes. Batches of cells from different cell passages were collected and analyzed. The level of XIST expression is stable between different cell passages (Fig. 5A). A high correlation of XIST expression (Pearson's coefficient, r = 0.88, p = 2.6 × 10− 8) was observed between the two different passages of individual cell lines. A strong correlation in KDM5C expression was also observed between the two different cell passages (Pearson's coefficient, r = 0.6, p = 0.0028) (Fig. 5B). As expected, KDM6A expression appeared to be more susceptible to variations between different cell cultures (Fig. S6D). We did not detect an increase of X chromosome DNA copies in the patients with high XIST expression, ruling out the presence of patients with Triple X syndrome in our samples (Fig. S6E).


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)

XIST and KDM5C expression across passages and alteration of epigenetic modifications in the patients. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR). XIST (A) and KDM5C (B) gene expression was examined in the first batch of lymphoblastoid cells (XIST-1 and KDM5C-1). After more than a month of continuous cell culture, the same set of genes was examined again in the second batch of the same cell lines with different cell passages (XIST-2 and KDM5C-2). A high correlation of XIST (Pearson's coefficient, r = 0.88, p = 2.6 × 10− 8) and KDM5C (Pearson's coefficient, r = 0.6, p = 0.0028) expression was observed between the two batches of cells with different passages. (C) Western blot analyses of KDM5C protein expression in the lymphoblastoid cells of female patients with recurrent major depression. A single band at 180 kD, the calculated size of human KDM5C protein, was detected. C: controls; D: recurrent major depression. β-actin was used as an internal control for normalization. (D) Consistent with increased mRNA expression, significantly higher KDM5C protein expression was found in the patients (t(22) = − 2.85, p < 0.01). (E) Lymphoblastoid cell lines from 4 female controls (black) and 4 female patients (red) with either recurrent major depression or mania and psychosis were selected for chromatin immunoprecipitation experiments. Six sites, separated by ~ 1 kb (except a 2 kb between 1 and 2) around the promoter of XIST gene, were examined by ChIP-QPCR. Multiple comparisons of Student's t-tests were corrected with FDR. Significantly more H3K27me3 was observed in the patients' lymphoblastoid cells at XIST (1) (t(6) = − 3.83, p < 0.05) and XIST (3) (t(6) = − 3.2, p < 0.05). A trend of more H3K27me3 at XIST (4) (t(6) = − 2.7, p < 0.1) was also observed. (F) Two sites around the promoter of KDM5C gene were also examined by CHIP-QPCR. H3K27me3 is significantly more enriched at KDM5C (1) (t(6) = − 3.39, p < 0.05) in female patients' lymphoblastoid cells.
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Related In: Results  -  Collection

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f0025: XIST and KDM5C expression across passages and alteration of epigenetic modifications in the patients. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR). XIST (A) and KDM5C (B) gene expression was examined in the first batch of lymphoblastoid cells (XIST-1 and KDM5C-1). After more than a month of continuous cell culture, the same set of genes was examined again in the second batch of the same cell lines with different cell passages (XIST-2 and KDM5C-2). A high correlation of XIST (Pearson's coefficient, r = 0.88, p = 2.6 × 10− 8) and KDM5C (Pearson's coefficient, r = 0.6, p = 0.0028) expression was observed between the two batches of cells with different passages. (C) Western blot analyses of KDM5C protein expression in the lymphoblastoid cells of female patients with recurrent major depression. A single band at 180 kD, the calculated size of human KDM5C protein, was detected. C: controls; D: recurrent major depression. β-actin was used as an internal control for normalization. (D) Consistent with increased mRNA expression, significantly higher KDM5C protein expression was found in the patients (t(22) = − 2.85, p < 0.01). (E) Lymphoblastoid cell lines from 4 female controls (black) and 4 female patients (red) with either recurrent major depression or mania and psychosis were selected for chromatin immunoprecipitation experiments. Six sites, separated by ~ 1 kb (except a 2 kb between 1 and 2) around the promoter of XIST gene, were examined by ChIP-QPCR. Multiple comparisons of Student's t-tests were corrected with FDR. Significantly more H3K27me3 was observed in the patients' lymphoblastoid cells at XIST (1) (t(6) = − 3.83, p < 0.05) and XIST (3) (t(6) = − 3.2, p < 0.05). A trend of more H3K27me3 at XIST (4) (t(6) = − 2.7, p < 0.1) was also observed. (F) Two sites around the promoter of KDM5C gene were also examined by CHIP-QPCR. H3K27me3 is significantly more enriched at KDM5C (1) (t(6) = − 3.39, p < 0.05) in female patients' lymphoblastoid cells.
Mentions: We investigated whether cell passages may alter expression of XIST, KDM5C, and KDM6A genes. Batches of cells from different cell passages were collected and analyzed. The level of XIST expression is stable between different cell passages (Fig. 5A). A high correlation of XIST expression (Pearson's coefficient, r = 0.88, p = 2.6 × 10− 8) was observed between the two different passages of individual cell lines. A strong correlation in KDM5C expression was also observed between the two different cell passages (Pearson's coefficient, r = 0.6, p = 0.0028) (Fig. 5B). As expected, KDM6A expression appeared to be more susceptible to variations between different cell cultures (Fig. S6D). We did not detect an increase of X chromosome DNA copies in the patients with high XIST expression, ruling out the presence of patients with Triple X syndrome in our samples (Fig. S6E).

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