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Epigenetic Control of Vasopressin Expression Is Maintained by Steroid Hormones in the Adult Male Rat Brain

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Epigenetic Control of Vasopressin Expression Is Maintained by Steroid Hormones in the Adult Male Rat Brain Epigenetic control of vasopressin expression is maintained by steroid hormones in the adult male rat brain Catherine J. Augera,b,1, Dylan Cossa, Anthony P. Augera,b, and Robin M. Forbes-Lormana aDepartment of Psychology and bNeuroscience Training Program, University of Wisconsin, Madison, WI 53706 Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved February 2, 2011 (received for review January 6, 2011) Although some DNA methylation patterns are altered by steroid AVP expression. Estradiol regulates AVP expression mainly by hormone exposure in the developing brain, less is known about acting upon neuronal estrogen receptors. Interestingly, castra- how changes in steroid hormone levels influence DNA methylation tion is known to increase estrogen receptor α (ERα) mRNA (14, patterns in the adult brain. Steroid hormones act in the adult brain 19). Therefore, castration decreases AVP but increases ERα to regulate gene expression. Specifically, the expression of the expression. As ER activation by estradiol is known to down- socially relevant peptide vasopressin (AVP) within the bed nucleus regulate ERα expression (14, 19), it is not surprising that cas- of the stria terminalis (BST) of adult brain is dependent upon tration increases ERα due to lowered ERα activation. This testosterone exposure. Castration dramatically reduces and tes- suggests that testosterone inversely regulates these two genes in tosterone replacement restores AVP expression within the BST. As the adult male brain, and possibly within the same cell. decreases in mRNA expression are associated with increases in As AVP expression is exquisitely responsive to steroid hor- DNA promoter methylation, we explored the hypothesis that AVP mones within the BST of the adult brain (14, 20), and as changes expression in the adult brain is maintained through sustained in DNA methylation patterns can influence gene expression, we epigenetic modifications of the AVP gene promoter. We find that hypothesized that the steroid dependence of AVP expression castration of adult male rats resulted in decreased AVP mRNA within the adult brain is maintained through epigenetic modifi- expression and increased methylation of specific CpG sites within cation (i.e., DNA methylation) of the AVP promoter region. In NEUROSCIENCE the AVP promoter in the BST. Similarly, castration significantly additionally, we expect that ERα promoter methylation will increased estrogen receptor α (ERα) mRNA expression and de- follow a pattern opposite to that of AVP promoter methylation. creased ERα promoter methylation within the BST. These changes Therefore, we assessed whether testosterone removal by castra- were prevented by testosterone replacement. This suggests that tion differentially altered AVP and ERα promoter methylation the DNA promoter methylation status of some steroid responsive patterns. The data here suggest that steroid hormones actively genes in the adult brain is actively maintained by the presence of maintain DNA methylation patterns in the adult brain, and that circulating steroid hormones. The maintenance of methylated or changes in steroid hormone levels result in changes in mRNA demethylated states of some genes in the adult brain by the pres- expression and DNA methylation promoter patterns of AVP and ence of steroid hormones may play a role in the homeostatic reg- ERα in the adult brain. ulation of behaviorally relevant systems. Results pigenetic modification of chromatin (e.g., changes in DNA Castration Effect on AVP mRNA Expression and Methylation. AVP Emethylation status), by either steroid hormone exposure or mRNA in BST. Our data replicate previous findings on testosterone changes in the social environment, can create changes in tran- regulation of AVP mRNA levels in adult male rats. That is, scription rates of a number of genes within the developing brain, castration (CX) significantly reduces AVP expression within the and in some cases these changes extend into adulthood (1–6). In BST of male rats compared with sham controls. We also con- adulthood, steroid hormones act to regulate the expression of firmed that testosterone replacement (CX+T) can reverse this steroid receptors as well as other factors in a fairly transient effect in adult male rats [F (2, 18) = 5.380, P = 0.015] (Fig. 1). manner (7). Recent findings in vitro have shown that DNA AVP methylation in BST. We then examined the methylation profile methylation patterns on some genes cycle back and forth from of the AVP promoter within the BST using two different methylated to unmethylated states within minutes (8, 9). This methylation sensitive restriction enzymes (MSREs) based on the supports the emerging concept that not all methylation patterns specific CpG sites bound by these enzymes on the AVP promoter are stable. Whether a change in methylation status plays a role in (Fig. 2, gray-shaded bases in each sequence). Using four differ- the regulation of gene expression in the adult brain is not well ent primer sets, we were able to target four individual CpG sites understood. We begin to elucidate this possibility by examining on the AVP promoter. We used the HpaII enzyme to bind three the hormonal maintenance of expression and DNA promoter distinct CCGG sequences on the AVP promoter. For the first methylation status of the socially relevant neuropeptide vaso- and third CCGG sequence that we targeted, located at bases pressin (AVP) in the adult brain. 1392 and 3895, using AVP promoter primer-targeted CpG site 1 The extrahypothalamic AVP system in the rat brain is highly and 3, respectively, we did not detect any change in relative sexually dimorphic and steroid responsive (10). Adult male rats have two times more AVP-expressing cells in the bed nucleus of the stria terminals (BST) compared with females (11, 12). AVP Author contributions: C.J.A. designed research; C.J.A., D.C., and R.M.F.-L. performed re- expression within this area is dependent upon gonadal hor- search; C.J.A. and A.P.A. contributed new reagents/analytic tools; C.J.A., D.C., and A.P.A. mones, as castration results in a significant decrease in AVP analyzed data; and C.J.A. wrote the paper. mRNA and protein expression, and testosterone replacement The authors declare no conflict of interest. restores AVP expression (13–15). The AVP cells within the BST This article is a PNAS Direct Submission. express receptors for androgens (16), estrogens (17), and pro- Freely available online through the PNAS open access option. gestins (18). Although testosterone reinstates AVP expression in 1To whom correspondence should be addressed. E-mail: [email protected]. the BST following castration (10), it is essentially estradiol, a This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. metabolite of testosterone, that is the major factor regulating 1073/pnas.1100314108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1100314108 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 the second CCGG site. Using AVP promoter primer-targeted CpG site 4, we found that relative methylation was significantly increased following castration, and importantly, this increase was prevented by replacement with testosterone 2 wk after castration [F (2, 25)=17.26, P ≤ 0.001; Figs. 2D and 3D]. Increased methylation of the AVP promoter region is associated with de- creased AVP mRNA levels. AVP mRNA in paraventricular nucleus of hypothalamus (PVN), and AVP methylation in PVN. As AVP in the BST is highly steroid re- sponsive, we examined AVP mRNA in another brain area that is less steroid responsive than the BST. We chose to examine AVP expression within the PVN; in this area, there was no statistically significant effect of castration or testosterone replacement on AVP mRNA (P > 0.05). Fig. 1. Castration effect on AVP mRNA in BST. Relative AVP mRNA expression As expected from the mRNA data, we did not find any sig- within the BST in each treatment group. As expected, AVP is significantly re- nificant changes in methylation profiles of the AVP gene (P > fi duced by CX and replacement with testosterone- lled capsules reinstates AVP 0.05; Fig, S1). We used the same restriction enzymes in the PVN expression in the BST (*P =0.015;n ≥ 6). Error bars represent SEM. as we did in the BST, and we also used the same primer sets corresponding to each enzyme cut site. There was no difference methylation in any of the groups [F (2, 26) = 0.0987, P = 0.906; in the methylation status of the AVP gene in the PVN using Figs. 2A and 3A; F (2, 26) = 0.251, P = 0.780; Figs. 2C and 3C]. primers for AVP promoter primer-targeted CpG site 1, 2, 3, or 4 P > With the second CCGG sequence that we targeted, located at ( 0.05 for each primer set). base 2243, using AVP promoter primer-targeted CpG site 2, we α ERα fi Castration Effect on ER mRNA Expression and Methylation. found that our treatment had a signi cant effect on methylation mRNA in BST. Previous studies have reported that castration of fi status. Methylation at this site was signi cantly increased in re- male rats, results in a significant increase in ER mRNA levels sponse to long-term castration, and returned to control levels in within the BST (19). Also, treatment with testosterone (21) or animals that were castrated and 2 wk later treated with testos- estradiol (19) reduces ER mRNA expression in the hypothala- terone [F (2, 24) = 4.681, P = 0.019; Figs. 2B and 3B]. Using the mus and BST, respectively. Our data replicate these previous BstUI enzyme, which binds to a CGCG sequence at base 4970 on findings. Castration results in significantly higher levels of ERα the AVP promoter, we found a similar methylation pattern to mRNA expression within the BST. Treatment with testosterone Fig. 2. Primer sequences used to assess relative methylation levels.
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