Acquisition of sexual receptivity: roles of chromatin acetylation, estrogen receptor-alpha, and ovarian hormones - PubMed (original) (raw)
Acquisition of sexual receptivity: roles of chromatin acetylation, estrogen receptor-alpha, and ovarian hormones
Paul J Bonthuis et al. Endocrinology. 2011 Aug.
Abstract
Sexually naïve, hormone-primed, C57BL/6J female mice are not receptive to mating attempts by conspecific males. Repeated experience with sexually active males and concurrent treatment with estradiol and progesterone gradually increases female receptivity over the course of five trials to maximal levels. Ovarian hormones activate their cognate nuclear steroid receptors estrogen receptor-α and progesterone receptor to induce female sexual receptivity. Nuclear receptors recruit coactivators of transcription that include histone acetyltransferases to hormone responsive genes. In this set of studies, we found that the histone deacetylase inhibitor sodium butyrate enhances the experiential acquisition of receptivity. Evidence is provided that the actions of sodium butyrate on receptivity require activated estrogen receptor-α and progesterone.
Figures
Fig. 1.
SB enhances the acquisition of receptivity in C57BL/6J females (mean ±
sem
). The LQ from OVX hormone-primed mice that either received SB in drinking water (n = 12) or untreated water (n = 11). A, Data for each of the five trails are presented. B, Data are presented as averages over all trials. 
, SB-treated females; 
, control females. *, Significantly different from own trial 1 baseline (P < 0.05); #, significantly greater than control group (P < 0.05).
Fig. 2.
SB does not rescue the LQ acquisition deficit in ERαknockout (ERKO) females (mean ±
sem
). The LQ data from hormone-primed ERKO females and their WT littermates that were either SB treated (SB) or not treated (Cont) are shown. Four groups with 10 females in each were formed and tested for receptivity. A, Data over five trials are shown. B, Data from the final trial are presented. , WT SB; , WT Cont; 
, ERKO SB; ○--, ERKO Cont. *, Significantly different from own trial 1 baseline (P < 0.05); $, significantly different from all other groups (P < 0.05). #, significantly different from WT females (P < 0.05).
Fig. 3.
Ovarian hormone replacement is essential for lordosis and SB enhancement of LQ (mean ±
sem
). The LQ in females treated with SB in their drinking water and either hormone primed for trials 1–5 (EB + P + SB) and injected with vehicle on trial 6 (G1, n = 5) or injected with vehicle for trials 1–5 (V + SB) and hormone primed only on trial 6 (G2, n = 5) is shown. Box around trial 6 in A indicates the hormone treatment shift. A, LQ data are given over all trials. , EB + P + SB in trials 1–5 and no hormone in trial 6 (G1); 
, V + SB trials 1–5 and hormone for trial 6 (G2). B, The LQ in trials 5 and 6 (black histogram, EB+P; white histogram, vehicle) are presented. *, Significantly different from own trial 1 baseline (P < 0.05); #, significantly higher than all the other values (P = 0.05).
Fig. 4.
Estradiol alone without P replacement is insufficient for lordosis and SB enhancement of LQ (mean ±
sem
). The LQ for the three groups of 10 females each is shown. One group was hormone primed with both estradiol and P (EB + P). Two other groups were primed with EB alone: one was SB treated (EB + SB), and the other was not (EB). A, LQ data over five trials are shown. B, The average LQ for each group is given over all five trials. , EB + P; 
, EB; 
, SB. *, Significantly different from own trial 1 baseline (P < 0.05); #, significantly different from other groups (P < 0.05).
Fig. 5.
Acetylation levels of histones in brain tissue from SB treated females. A, A representative Western blot of AcH3 subunit and total H4 subunit loading control from whole-brain histone extractions of WT and ERα knockout (ERKO) littermate females both treated with SB and untreated (Cont). For each group, three individuals are shown. B, Mean ±
sem
level of AcH3 normalized to H4 in whole-brain histone and expressed as a fraction of the mean WT Cont levels (n = 6 per treatment group). C, Mean ±
sem
level of AcH3 normalized to total H3 of hypothalamic tissue from EB (Cont) and EB + SB (SB) (n = 5 in each group). *, Significantly larger than Cont groups (P < 0.05).
Fig. 6.
Model for potential mechanism of estradiol and P signaling and histone deacetylase inhibition on receptivity. In the top panel, nuclear steroid receptors (NR) are not bound to ligand and do not occupy the DNA (straight black lines) promoters of estrogen- and P-responsive genes. In this transcriptionally inactive state, the chromatin is hypoacetylated, the RNA polymerase-II (Pol-II) is not recruited to the transcriptional start site, and the receptivity-promoting gene mRNA is expressed at low levels. In the bottom panel, ligand-activated (E/P) nuclear receptors dimerize and bind to estrogen and P response elements (open boxes), recruit coactivators (CoAct) including HAT to the promoter, cause acetylation (Ac) of histone (cylinders) tails and/or NR (AcNR), and recruit the basal transcription machinery and Pol-II to the transcription start site (TSS) to increase the expression of receptivity-promoting genes. Loss of ligand binding returns the genes to an inactive state in part by HDAC corepressor activity. HDAC inhibitors like SB impede the dynamic removal of acetyl groups leading to hyperacetylation that allows for increased and/or prolonged transcription of genes in the active state.
References
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