The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder

N Dubey, J F Hoffman, K Schuebel, Q Yuan, P E Martinez, L K Nieman, D R Rubinow, P J Schmidt, D Goldman, N Dubey, J F Hoffman, K Schuebel, Q Yuan, P E Martinez, L K Nieman, D R Rubinow, P J Schmidt, D Goldman

Abstract

Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and addback clinical trial, and controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (for example, gene transcription) and protein (for example, RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared with the controls, and with significant effects for MTF2, PHF19 and SIRT1 (P<0.05). RNA and protein expression of the 13 ESC/E(Z) complex genes were individually quantitated. This pattern of increased ESC/E(Z) mRNA expression was confirmed in a larger cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs with MTF2, PHF19 and SIRT1 all significantly decreased (P<0.05). Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in controls only, and decreased by estradiol in PMDD LCLs. These findings demonstrate that LCLs from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated condition and in response to ovarian hormones. Dysregulation of ESC/E(Z) complex function could contribute to PMDD.

Trial registration: ClinicalTrials.gov NCT00001259 NCT00001322.

Conflict of interest statement

The Authors have no potential conflicts of interest or financial support regarding this manuscript.

Figures

Figure 1. LCL treatments and analyses
Figure 1. LCL treatments and analyses
Flow chart of LCL experiments. Blood is collected from women with PMDD or asymptomatic Controls and transformed into LCLs with Epstein Barr virus. Cells are then left untreated or treated with hormone (estradiol or progesterone, 100 nM each) and undergo RNA-sequencing. Pathway analyses were applied to results, and selected genes from the indicated LCL groups are followed up with qRT-PCR and protein analysis via ProteinSimple©.
Figure 2. mRNA and protein expression for…
Figure 2. mRNA and protein expression for hormone receptors and ESC/E(Z) Complex genes comparing untreated Control and PMDD lymphoblastoid cell lines
All graphs are presented as group mean ± SEM. (A–F) Student’s t-test was performed for each comparison. (A) qRT-PCR analysis of mRNA expression for hormone receptors ESR1, ESR2, PGRMC1, and PGRMC2 in lymphoblastoid cell lines (LCLs), n=15. Relative gene expression levels were calculated for ∆CT value with β-actin as the reference control for normalization; note a lower ∆CT value indicates higher expression. Both ESR1 and PGRMC1 were significantly higher in the PMDD group than the Control group (*p<0.05), and ESR2 was higher at a trend level of significance in the PMDD group than the Control group (#p<0.1). (B) Verification of β-actin as a normalizing protein for ProteinSimple© western analysis of protein expression in LCLs. The chemiluminescense ratio of β-actin over the ProteinSimple© Loading Control (PSCon) was calculated for each group and no significant difference was found (n=7, t12=0.02, p=0.9). (C–F) ProteinSimple© western analysis of protein expression for hormone receptors ESR1, ESR2, PGRMC1, and PGRMC2 (n=7). Target protein chemiluminescense was normalized to β-actin or PSCon if there was band interference with β-actin, as was the case for ESR2 and PGRMC2. There were no significant differences for any of the proteins. For (B–F), representative images of protein “bands” from the Compass software are shown below each group. (G–H) All graphs are calculated as percent change of values of the PMDD group from the Control group mean. Statistical analysis comes from Student’s t-test of the original group means (see Supplemental Figure 2). (G) Percent change from control of mRNA expression via RNAseq for the 13 genes of the ESC/E(Z) complex (n=9–10). Both MTF2 and SIRT1 were significantly higher in the PMDD group than the Control group (*p<0.05), and EED, HDAC2, and SUZ12 were higher at a trend level of significance in the PMDD group than the Control group (#p<0.1), while PHF19 was lower at a trend level of significance in the PMDD group than the control group (#p<0.1). (H) Percent change from control of mRNA expression via qRT-PCR for the 13 genes of the ESC/E(Z) complex (n=29–30). HDAC2 (t43=2.6), MTF2 (t37=3.7), SIRT1 (t46=3.2), and SUZ12 (t42=2.1) were significantly higher in the PMDD group than the Control group (*p<0.05), and RBBP7 (t33=1.8) was trending higher in the PMDD group than the Control group (#p<0.1). (I) Percent change from control of protein expression via ProteinSimple© western analysis for select genes of the ESC/E(Z) complex (n=7). NT indicates that protein was not tested. MTF2 (t11=3.4), PHF19 (t12=2.5), and SIRT1 (t11=3.2) were significantly lower in the PMDD group than the Control group (*p<0.05).
Figure 3. Selected ESC/E(Z) gene expressions from…
Figure 3. Selected ESC/E(Z) gene expressions from RNAseq: ANOVAs comparing untreated and estradiol- or progesterone-treated Control and PMDD lymphoblastoid cell lines
All graphs are presented as group mean ± SEM using RPKM values from RNA-sequencing. Two-way ANOVAs were performed for each gene of interest, followed by Sidak’s multiple comparisons post-hoc test in cases of a significant interaction. Untreated Control and PMDD lymphoblastoid cell lines compared with estradiol treatment (A) or progesterone treatment (B-F). (A) For JARID2 there was a significant interaction effect between diagnosis and estradiol treatment (F1,24=5.5, *p<0.05). Expression was significantly decreased after estradiol only in the PMDD group (t24=2.5, adjusted p-value<0.05). (B) For EED there was a significant interaction effect between diagnosis and progesterone treatment (F1,29=6.8, *p<0.05). Expression was significantly increased after progesterone only in the Control group (t29=2.8, adjusted p-value<0.05). (C) For EZH2 there was a significant interaction effect between diagnosis and progesterone treatment (F1,29=4.8, *p<0.05). Expression was significantly increased after progesterone only in the Control group (t29=2.4, adjusted p-value<0.05). (D) For MTF2 there was a significant interaction effect between diagnosis and progesterone treatment (F1,29=9.2, *p<0.05). Expression was significantly increased after progesterone only in the Control group (t29=2.7, adjusted p-value<0.05). Additionally, there was also a significant diagnosis effect (F1,29=5.5, *p<0.05) where MTF2 is more highly expressed in the PMDD group than the Control group (post-hoc untreated Control vs untreated PMDD t29=4.1, p<0.001). (E) For PHF19 there was a significant diagnosis effect (F1,29=16.1, *p<0.05) where expression is lower in the PMDD group compared with the Control group, but there was no interaction effect between diagnosis and progesterone treatment (F1,29=0.1, p=0.7). (E) For SIRT1 there was a significant diagnosis effect (F1,29=13.1, *p<0.05) where expression was higher in the PMDD group compared to the Control group, but there was no interaction effect between diagnosis and progesterone treatment (F1,29=0.5, p=0.5).
Figure 4. GeneMANIA interaction analysis of ESC/E(Z)…
Figure 4. GeneMANIA interaction analysis of ESC/E(Z) and steroid hormone receptor genes
GeneMANIA (genemania.org) was used to generate a gene network analysis inputting the 13 genes of the ESC/E(Z) complex (AEBP2, EED, EZH1, EZH2, HDAC2, JARID2, MTF2, PHF1, PHF19, RBBP4, RBBP7, SIRT1, SUZ12) and the 4 hormone receptor genes (ESR1, ESR2, PGRMC1, PGRMC2), whose expression was identified in LCLs. Genes and targets are included in the network for the input genes based on weights of interactions with the input genes, determined automatically by linear regression. Black circles indicate the input genes. Gray circles indicate additional genes identified in the network – a larger circle reflects a higher rank of connection with the input genes. Diamonds indicate miRNA or transcription factor targets. A thicker connecting bar between nodes reflects a stronger relationship between those two nodes. (A) The expanded network based on a search of these 17 input genes (September, 2015). The strongest relationships driving this network are Predicted Interactions (44.22% weight) and Physical Interactions (41.35% weight). (B) Selection of HDAC2 and highlighting its interactions within the predicted network. HDAC2 shows interactions with 9 of the 13 genes of the ESC/E(Z) complex (7 of them physical), as well as several other genes in the network. Importantly, it is the only component of the ESC/E(Z) complex that interacts with a receptor for both estradiol (ESR1) and progesterone (PGRMC2).

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