State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China.
Int J Mol Sci. 2023 Nov 17;24(22):16442. doi: 10.3390/ijms242216442.
GNAQ, a member of the alpha subunit encoding the q-like G protein, is a critical gene in cell signaling, and multiple studies have shown that upregulation of gene expression ultimately inhibits the proliferation of gonadotropin-releasing hormone (GnRH) neurons and GnRH secretion, and ultimately affects mammalian reproduction. Photoperiod is a key inducer which plays an important role in gene expression regulation by affecting epigenetic modification. However, fewer studies have confirmed how photoperiod induces epigenetic modifications of the gene. In this study, we examined the expression and epigenetic changes of GNAQ in the hypothalamus in ovariectomized and estradiol-treated (OVX+E) sheep under three photoperiod treatments (short photoperiod treatment for 42 days, SP42; long photoperiod treatment for 42 days, LP42; 42 days of short photoperiod followed by 42 days of long photoperiod, SP-LP42). The results showed that the expression of GNAQ was significantly higher in SP-LP42 than in SP42 and LP42 ( < 0.05). Whole genome methylation sequencing (WGBS) results showed that there are multiple differentially methylated regions (DMRs) and loci between different groups of GNAQ. Among them, the DNA methylation level of DMRs at the CpG1 locus in SP42 was significantly higher than that of SP-LP42 ( < 0.01). Subsequently, we confirmed that the core promoter region of the gene was located with 1100 to 1500 bp upstream, and the DNA methylation level of all eight CpG sites in SP42 was significantly higher than those in LP42 ( < 0.01), and significantly higher than those in SP-LP42 ( < 0.01), except site 2 and site 4 in the first sequencing fragment ( < 0.05) in the core promoter region. The expression of acetylated histone H3 was significantly higher than that of the control group under three different photoperiods ( < 0.01); the acetylation level of sheep hypothalamic GNAQ genomic protein H3 was significantly lower under SP42 than under SP-LP42 ( < 0.05). This suggests that acetylated histone H3 binds to the core promoter region of the gene, implying that GNAQ is epigenetically regulated by photoperiod through histone acetylation. In summary, the results suggest that photoperiod can induce DNA methylation in the core promoter region and histone acetylation in the promoter region of the gene, and hypothesize that the two may be key factors in regulating the differential expression of GNAQ under different photoperiods, thus regulating the hypothalamus-pituitary-gonadal axis (HPGA) through the seasonal estrus in sheep. The results of this study will provide some new information to understand the function of epigenetic modifications in reproduction in sheep.
GNAQ 是 alpha 亚基编码的 q 样 G 蛋白的成员，是细胞信号转导中的关键基因，多项研究表明，基因表达的上调最终抑制了促性腺激素释放激素 (GnRH) 神经元的增殖和 GnRH 的分泌，最终影响了哺乳动物的繁殖。光周期是一种关键的诱导因子，通过影响表观遗传修饰在基因表达调控中发挥重要作用。然而，较少的研究证实了光周期如何诱导基因的表观遗传修饰。在这项研究中，我们研究了在三种光周期处理下（卵巢切除和雌二醇处理 42 天的短光周期处理，SP42；42 天的长光周期处理，LP42；42 天的短光周期后紧接着 42 天的长光周期处理，SP-LP42），下丘脑 GNAQ 在去卵巢和雌二醇处理的（OVX+E）绵羊中的表达和表观遗传变化。结果表明，SP-LP42 组的 GNAQ 表达明显高于 SP42 和 LP42 组（<0.05）。全基因组甲基化测序（WGBS）结果表明，不同 GNAQ 组之间存在多个差异甲基化区域（DMRs）和基因座。其中，SP42 中 CpG1 基因座的 DMRs 的 DNA 甲基化水平明显高于 SP-LP42（<0.01）。随后，我们证实了基因的核心启动子区域位于上游 1100 至 1500bp 处，并且 SP42 中所有八个 CpG 位点的 DNA 甲基化水平明显高于 LP42（<0.01），并且明显高于 SP-LP42（<0.01），除了第一个测序片段（<0.05）中位点 2 和位点 4 的核心启动子区域。在三种不同的光周期下，乙酰化组蛋白 H3 的表达明显高于对照组（<0.01）；在 SP42 下，绵羊下丘脑 GNAQ 基因组蛋白 H3 的乙酰化水平明显低于 SP-LP42（<0.05）。这表明乙酰化组蛋白 H3 结合到基因的核心启动子区域，暗示 GNAQ 是通过组蛋白乙酰化被光周期调控的。综上所述，结果表明光周期可以诱导基因核心启动子区域的 DNA 甲基化和启动子区域的组蛋白乙酰化，并假设这两个可能是调节不同光周期下 GNAQ 差异表达的关键因素，从而通过绵羊的季节性发情调节下丘脑-垂体-性腺轴（HPGA）。本研究的结果将为理解绵羊生殖中表观遗传修饰的功能提供一些新信息。
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