Fetal alcohol exposure alters proopiomelanocortin gene expression and hypothalamic-pituitary-adrenal axis function via increasing MeCP2 expression in the hypothalamus.
- Authors
- Gangisetty, Omkaram; Bekdash, Rola; Maglakelidze, George; Sarkar, Dipak K
- Year
- 2014
- Journal
- PloS one
- PMID
- 25409090
- DOI
- 10.1371/journal.pone.0113228
- PMCID
- PMC4237387
Proopiomelanocortin (POMC) is a precursor gene of the neuropeptide Ξ²-endorphin in the hypothalamus and is known to regulate various physiological functions including stress response. Several recent reports showed that fetal alcohol exposure programs the hypothalamus to produce lower levels of POMC gene transcripts and to elevate the hypothalamic-pituitary-adrenal (HPA) axis response to stressful stimuli. We investigated the role of methyl CpG binding protein (MeCP2) in the effects of prenatal ethanol on POMC gene expression and hypothalamic-pituitary-adrenal (HPA) axis function. Pregnant Sprague Dawley rats were fed between GD 7 and 21 with a liquid diet containing 6.7% alcohol, pair-fed with isocaloric liquid diet, or fed ad libitum with rat chow, and their male offsprings were used at 60 days after birth in this study. Fetal alcohol exposure reduced the level of POMC mRNA, but increased the level of DNA methylation of this gene in the arcuate nucleus (ARC) of the hypothalamus where the POMC neuronal cell bodies are located. Fetal alcohol exposed rats showed a significant increase in MeCP2 protein levels in POMC cells, MeCP2 gene transcript levels as well as increased MeCP2 protein binding on the POMC promoter in the arcuate nucleus. Lentiviral delivery of MeCP2 shRNA into the third ventricle efficiently reduced MeCP2 expression and prevented the effect of prenatal ethanol on POMC gene expression in the arcuate nucleus. MeCP2-shRNA treatment also normalized the prenatal ethanol-induced increase in corticotropin releasing hormone (CRH) gene expression in the hypothalamus and elevated plasma adrenocorticotrophic hormone (ACTH) and corticosterone hormone responses to lipopolysaccharide (LPS) challenge. These results suggest that fetal alcohol programming of POMC gene may involve recruitment of MeCP2 on to the methylated promoter of the POMC gene to suppress POMC transcript levels and contribute to HPA axis dysregulation.
POMC gene expression and methylation changes in MBH of fetal alcohol exposed rat offspring. A. POMC mRNA levels in MBH of AD, PF and AF rat offspring were measured by quantitative RT-PCR and the amounts were normalized with GAPDH values and expressed as relative mRNA levels. Data are mean Β± SEM (n = 6) and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; *, P<0.05, AF vs AD or PF. B. POMC promoter methylation levels in MBH of AD, PF and AF rat offspring were assayed by real time methylation specific PCR. POMC promoter methylation levels were measured as ratios of methylated verses unmethylated DNA values. Data are mean Β± SEM (n = 6) and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; ***, P<0.001, AF vs AD or PF.
LLM interpretation
This figure consists of two bar charts comparing POMC gene expression and methylation in the MBH of three rat offspring groups: AD, PF, and AF. Panel A shows that relative POMC mRNA levels are significantly lower in the AF group compared to AD and PF groups (*P < 0.05). Panel B shows that the POMC promoter methylation ratio is significantly higher in the AF group compared to the AD and PF groups (***P < 0.001).
Changes in MeCP2 gene and protein levels in MBH of fetal alcohol exposed rat offspring. A. MeCP2 mRNA levels in MBH of AD, PF and AF rat offspring. MeCP2 mRNA levels were measured by quantitative RT-PCR and the amounts were normalized with GAPDH values and expressed as relative mRNA levels. Data are mean Β± SEM (n = 6) and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; *, P<0.05, AF vs. AD or PF. B. A representative western blot gel demonstrating changes in MeCP2 protein levels (top) and actin levels (loading control, bottom) in MBH of AD, PF and AF rat offspring along with quantification measurements were represented as relative protein level (MeCP2/actin). Data are mean Β± SEM (n = 6) and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; **, P<0.01, AF vs. AD or PF. C. MeCP2 protein levels in Ξ²-endorphin neurons in the ARC of AD, PF and AF rat offspring were measured by double immunofluorescence methods (MeCP2 proteins are shown in green and Ξ²-endorphin shown in red). Representative photographs show double-labeled cells in each group. Histograms show the mean Β± SEM (n = 6) values of percent Ξ²-EP cells expressing MeCP2 and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; ***, P<0.001, AF vs. AD or PF.
LLM interpretation
This figure consists of three panels (A-C) comparing MeCP2 levels in the MBH of AD, AF, and PF rat offspring. Panel A shows a bar chart of relative MeCP2 mRNA levels, and Panel B includes a western blot and corresponding bar chart for relative MeCP2 protein levels, both showing a significant increase in the AF group compared to AD and PF (*P<0.05 and **P<0.01, respectively). Panel C displays double immunofluorescence images and a bar chart showing a significantly higher percentage of $\beta$-endorphin (BEP) cells expressing MeCP2 in the AF group (***P<0.001).
Changes in MeCP2 binding onto POMC promoter in ARC and PVN of fetal alcohol exposed rat offspring. A. Schematic representation of POMC promoter with CpG sites and primers flanking MeCP2 binding site. B. The levels of MeCP2 binding on POMC promoter in ARC and PVN of AD, PF and AF rat offspring were measured by ChIP assay. MeCP2 bound DNA pulled by its specific antibody was amplified by real time PCR using primers specific for the POMC promoter. MeCP2 enriched DNA was normalized with GAPDH and expressed as fold enrichment (MeCP2/GAPDH). AD and AF are ARC samples of ad libitum-fed and alcohol-fed rats. ADP and AFP are PVN samples of ad libitum-fed and alcohol-fed rats. Data are mean Β± SEM (n = 6) and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; *, P<0.05, AF vs. AD; a, P<0.001, ADP and AFP versus AD or AF.
LLM interpretation
Figure A is a schematic diagram of the POMC promoter showing CpG sites and the locations of MSP and PCR primers. Figure B is a bar chart showing MeCP2 fold enrichment (normalized to GAPDH) in the ARC and PVN of ad libitum-fed (AD, ADP) and alcohol-fed (AF, AFP) rat offspring. MeCP2 binding is significantly higher in AF compared to AD rats in the ARC (*P<0.05), and overall binding levels are significantly higher in the PVN (ADP and AFP) compared to the ARC (AD and AF) (a, P<0.001).
Effects of lentiviral knockdown of MeCP2 on POMC gene expression levels in fetal alcohol exposed rat offspring. A. A representative western blot gel showing MeCP2 protein levels (top) and actin levels (bottom) in MBH of scr sh (scr) or MeCP2 sh (MeCP) RNA-treated AD, PF and AF rat offspring. Histograms showing MeCP2 and actin ratio values in MBH of AD, PF and AF rats.treated with scr sh or MeCP2 sh RNA. Data are mean Β± SEM (n = 6) and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; *, P<0.05, MeCP2 sh vs. scr-sh; a, P<0.05, AF vs. AD or PF. B. POMC mRNA levels in MBH of scr-sh and MeCP2 sh RNA of AD, PF and AF rat offspring. POMC mRNA amounts were normalized with GAPDH and expressed as relative mRNA level. Data are mean Β± SEM (n = 6) and were analyzed using one-way ANOVA with Newman-Keuls post-hoc test; *, P<0.05, AF- vs. AD- or PF-scr-sh-treated groups; a, P<0.05, MeCP2 sh vs. scr-sh (AF group).
LLM interpretation
Figure A consists of a representative western blot and a corresponding bar chart showing that MeCP2 protein levels are significantly reduced in AD, PF, and AF groups treated with MeCP2 shRNA compared to scr-sh controls (*P<0.05), with AF-Scr showing significantly higher levels than AD-Scr or PF-Scr (a, P<0.05). Figure B is a bar chart showing relative POMC mRNA levels, where AF-Scr levels are significantly lower than AD-Scr or PF-Scr (*P<0.05), and MeCP2 knockdown significantly increases POMC mRNA levels specifically in the AF group (a, P<0.05). Both charts display data as mean Β± SEM.
Effect of MeCP2 knockdown on stress axis responsiveness in fetal alcohol exposed rat offspring. A. CRH mRNA levels in the MBH of scr sh- or MeCP2 sh RNA-treated AD, PF and AF rat offspring. CRH mRNA amounts were normalized with GAPDH and expressed as relative mRNA level. Data are mean Β± SEM (n = 6) and were analyzed using two-way ANOVA with Newman-Keuls post-hoc test; *, P<0.05, AF vs. AD or PF groups; a, P<0.05, MeCP2 sh vs. scr-sh (AF group). B. ACTH levels in plasma of AD, PF or AF rats treated with either scr sh or MeCP2-sh RNA at 0 h and 2 h after LPS treatment. Data are mean Β± SEM (n = 6) and were analyzed using two-way ANOVA with Bonferroni post-hoc test; *, P<0.05, AF vs. AD or PF (within Scr sh treatment groups); a, P<0.05, MeCP2 sh vs. scr-sh (AF groups). C. Corticosterone levels in AD, PF or AF rats treated with either scr sh or MeCP2 sh RNA at 0 h and 2 h after LPS treatment. Data are mean Β± SEM (n = 6) and were analyzed using two-way ANOVA with Bonferroni post-hoc test; *, P<0.05, AF vs. AD or PF (within Scr sh treatment groups); a, P<0.05, MeCP2 sh vs. scr-sh (AF groups).
LLM interpretation
This figure consists of three bar charts (A, B, and C) comparing the effects of MeCP2 knockdown (Mecp2-sh) versus a control (Scr-sh) across three rat offspring groups: AD, PF, and AF. Panel A shows that CRH mRNA levels in the MBH are significantly elevated in the AF group compared to AD and PF, a trend partially attenuated by MeCP2 knockdown. Panels B and C show that plasma ACTH and corticosterone levels significantly increase 2 hours after LPS treatment specifically in the AF Scr-sh group, with MeCP2 knockdown significantly reducing these responses. Statistical significance is indicated by asterisks (*) for AF vs. AD/PF and the letter 'a' for MeCP2-sh vs. Scr-sh within the AF group.
A Model illustrating the role of promoter methylation and MeCP2 binding in regulation of POMC expression following fetal alcohol exposure.In control rat offspring transcription factor binds to hypomethylated POMC promoter and activates transcription (top). Fetal alcohol exposure promotes hypermethylation of the POMC promoter and recruits MeCP2. MeCP2 binding to CpG methylated POMC promoter prevents the transcription factor's ability to bindto activate gene transcription.
LLM interpretation
This is a schematic diagram illustrating the regulation of POMC expression in control rats versus those with fetal alcohol exposure. In control rats, a transcription factor (TF) binds to a hypomethylated promoter, leading to increased POMC expression. Following fetal alcohol exposure, the promoter becomes hypermethylated and recruits MeCP2, which blocks TF binding and results in decreased POMC expression.
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