Abstract
Background: Pulsatile pituitary gonadotropin secretion governed by hypothalamic gonadotropin-releasing hormone (GnRH) is essential for the pubertal onset. The epigenetic mechanism underlying the activation of GnRH-dependent regulatory axis in hypothalamus remains elusive. This study aims to explore the potential correlation between the signature of DNA (hydroxyl)methylation and pubertal process.Methods: Hypothalamic arcuate nucleus (ARC) of mouse at early (4-weeks) and late pubertal (8-weeks) stages underwent RNA-, RRBS-, and RRHP-seq to investigate the genome-wide profiles of transcriptome, differential DNA methylation and hydroxymethylation.Results: A series of differential expressed genes (DEGs) involved in sexual development could be separated into three subgroups with the significant difference of DNA methylation or hydroxymethylation or both in promoter regions. Compared to DNA methylation, DNA hydroxymethylation partook in more signaling pathways including synapse morphology, channel activity and glial development, which could enhance transsynaptic change and glia-to-neuron communication to faciliate GnRH release. The correlation between transcription and these epigenetic modifications indicated that DNA hydroxymethylation impacted with gene transcription independently of DNA methylation spanning puberty.Conclusion: Our results characterized the hydroxymethylation pattern and provided an insight into the novel epigenetic regulation on gene expression during pubertal process.
Highlights
Pubertal development is a multi-factorial process accompanied by maturity of skeletal height, growth spurt, and a myriad of hormonal changes involving genetic, nutritional, socioeconomic, and environmental factors in a systematic manner leading to reproductive maturation
The secretion of gonadotropin-releasing hormone (GnRH) in hypothalamus is majorly regulated by KiSS-1 metastasis suppressor (Kiss1) and Kiss1 receptor (Kiss1r, known as GPR54)
Kiss1 neurons of the arcuate nucleus (ARC) in the hypothalamus seem to be essential for pulsatile GnRH release in both sexes
Summary
Pubertal development is a multi-factorial process accompanied by maturity of skeletal height, growth spurt, and a myriad of hormonal changes involving genetic, nutritional, socioeconomic, and environmental factors in a systematic manner leading to reproductive maturation. Pubertal development is governed by the hypothalamic–pituitary–gonadal (HPG) axis, and begins with hypothalamic gonadotropin-releasing hormone (GnRH) neurons. The pulsatile secretion of GnRH from the hypothalamus stimulates on the gonadotroph cells of the pituitary gland to secrete gonadotropins, LH and FSH, and the gonadotropins stimulate the production of estrogen from the ovaries in females, and testosterone from the testes in males (Chulani and Gordon, 2014). Kiss neurons of the arcuate nucleus (ARC) in the hypothalamus seem to be essential for pulsatile GnRH release in both sexes. Transcriptional activation of these genes was considered as a core mechanism underlying the puberty initiation, which was precipitated by epigenetic cues (Ojeda and Lomniczi, 2014). Pulsatile pituitary gonadotropin secretion governed by hypothalamic gonadotropin-releasing hormone (GnRH) is essential for the pubertal onset. This study aims to explore the potential correlation between the signature of DNA (hydroxyl)methylation and pubertal process
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