DNA Methylation Regulating Activation of the Hypothalamic-Piuitary-Gonadal Axis in Patients with Delayed Puberty

ABSTRACT: Delayed puberty in humans is frequently an inherited condition with a clear genetic basis, previously linked to coding region sequence variation in gonadotropin-releasing hormone (GnRH) pathways genes. However, many patients do not have an identifiable genetic variant responsible for their delayed puberty and the role of epigenetic modifiers of human pubertal timing has been minimally explored. Robust evidence has been provided that the timing of puberty in animal models is regulated by an epigenetic mechanism of transcriptional repression. In view of the unique dynamic activity of the hypothalamic-pituitary-gonadal axis, changes in DNA methylation are highly likely to play a regulatory role in pubertal onset and timing. Genome wide DNA methylation was detected using the Illumina EPIC array, for patients (n=92) with delayed puberty who had no previously identified genetic cause for the condition, and related unaffected controls (n=20).This revealed differentially methylated CpG sites linked to key genes involved in upstream regulation of GnRH signaling, including TAC3, SIRT1, PDYN, KMT2A, NELL2 and KAT2B, all of which had increased DNA methylation, along with NOS1 and ZNF573 which had decreased methylation in individuals with delayed puberty compared to controls. These differentially methylated CpG sites were found in either enhancer or promoter regions of their corresponding genes. The top five differentially methylated enhancer or promoter associated CpG sites, defined by q value, identifed novel candidates genes involved in delayed puberty, including CADPS2. Over representation analysis identified multiple KEGG pathways previously associated with growth dysfunction as significantly altered. These included the cAMP pathway, the neuroactive ligand-receptor interaction pathway and growth hormone synthesis pathway. Differential methylation of genes related to BMI was observed in delayed compared to normal pubertal timing, but it was not specific to patients with low or high BMI. Subsequently, pathogenic exonic variants in the genes associated with the top 10 CpG enhancer and promoter sites were identified in patients from additional cohorts with delayed puberty. These findings support that changes in DNA methylation of key genes involved in GnRH regulation contribute to the phenotype of human delayed puberty.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338266 | GEO | 2026/07/31

REPOSITORIES: GEO