Abstract
Although selection of the early age at puberty in gilts will make for a favorable effect on the reproductivity of sow, a large proportion of phenotypic variation in age at puberty of gilts cannot be explained by genetics. Previous studies have implicated hypothalamic DNA methylation in the onset of puberty in mammals. However, the underlying molecular mechanism regarding the regulation of the onset of puberty has remained largely unexplored in gilts. Herein, the genome-scale DNA methylation of hypothalamus was acquired, using the reduced representation bisulfite sequencing, to compare and describe the changes of DNA methylation across Pre-, In- and Post-pubertal gilts. In this study, the average methylation levels of CpGs and CpHs (where H = C, T, or A) in CpG islands- and gene-related regions were gradually decreased in hypothalamic methylomes during the pubertal transition. Comparisons of Pre- vs. In-, In- vs. Post-, and Pre- vs. Post-pubertal stage revealed that there were 85726, 92914, and 100421 differentially methylated CpGs and 5940, 14804, and 16893 differentially methylated CpHs (where H = C, T, or A) in the hypothalamic methylomes. The methylation changes of CpHs were more dynamic than that of CpGs, and methylation changes of CpGs and CpHs were likely to be, respectively, involved in the developmental processes of reproduction and the molecular processes of cellular communications in the hypothalamus. Moreover, methylation changes of CpHs were observed to overrepresent in the quantitative trait loci of age at puberty, and the biological function of these CpH methylation changes was enriched in the pancreas development in gilts. Furthermore, the mRNA levels of several differentially CpG or CpH methylated genes related to the transcription of RNA II polymerase, GnRH signaling pathway, Estrogen signaling pathway, PI3K-AKt signaling pathway, and Insulin signaling pathway, including MAX, MMP2, FGF11, IGF1R, FGF21, and GSK3B, were significantly changed across these pubertal stages in the hypothalamus. These results will help our understanding of how DNA methylation contributes to phenotypic variation of age at puberty.
Highlights
In female pigs, the onset of puberty is widely thought to be the processes of sexual maturations of gilts to be capable of reproduction
We found that the mRNA levels of MAX (Figure 8A), MMP2 (Figure 8B), and FGF11 (Figure 8C), which were the DMC regarding genes and associated with the transcription of RNA II polymerase, gonadotropin-releasing hormone (GnRH) signaling pathway and Estrogen signaling pathway, were significantly changed across Pre, In, and Post-puberty in hypothalamus
GSK3B, which was one of genes of Insulin signaling pathway6 and associated with age of puberty in cattle (Fortes et al, 2013), displayed the lowest mRNA level in In-puberty (Figure 8F). These results indicated that methylation changes of CpGs were involved in the maintenance of molecular function within cellular communications during the initiation of puberty in gilts
Summary
The onset of puberty is widely thought to be the processes of sexual maturations of gilts to be capable of reproduction. With the intensive artificial selection for growth rate and lean meat, recent studies have suggested that approximately 30% of gilts are culled due to the delayed puberty (Stancic et al, 2009, 2011) with failure to display the first estrus by 240 days (Nonneman et al, 2014), which is consequent in a heavily economic burden on the modern commercial farms. Using the imputed whole genome sequences, Xin et al (2018) identified 2339 SNPs which were associated with pubertal reproductive failure, explaining 16% of the phenotypic variances. These studies suggest that genetic factors only can explain and account for ∼16% of the phenotypic variances of age at puberty in pigs. Changes of DNA methylation induced by 5-azacytidine have been demonstrated to disrupt the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and delay the onset of puberty (Lomniczi et al, 2013, 2015), suggesting that DNA methylation plays a vitally regulatory role in the onset of puberty and may contribute to the phenotypic variation of age at puberty in pigs
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