ESPE Abstracts

Background: Although the transition from the pre-pubertal condition to puberty occurs physiologically within a bounded age range, recent data indicate a central role for epigenetics in the regulation of several genes that could mediate an alteration of pubertal onset. Moreover, changes occurring during this developmental stage have often been associated with susceptibility to a wide range of diseases in later life. To identify changes in DNA methylation profile associated with the timing of human puberty, we compared genome-wide DNA methylation patterns of three different groups of girls: with central precocious puberty (CPP), prepubertal, pubertal girls.

Methods: Infinium Methylation EPIC BeadChip technology was used to obtain genome wide DNA methylation levels. We focused our studies on peripheral blood leukocytes from 20 female patients with idiopathic central precocious puberty (CPP) and 30 healthy girls (15 pre- and 15 pubertal). MKRN3 gene screening was performed in all girls with CPP without detecting significant mutations.

Results: Analysing methylation changes associated with normal puberty in healthy pre- and pubertal girls, we identified 1006 differentially methylated CpG sites (DM-CpGs), most of which (86%) were hypermethylated in pre-pubertal controls. Some of these DM-CpGs reside in genes associated with the age of menarche or transcription factors involved in the process of pubertal development. Analysis of methylome changes in CPP patients showed 65% and 55% hypomethylated CpG sites compared with pre-pubertal and pubertal controls, respectively. Interestingly, our results revealed the presence of 38 differentially methylated genes encoding for zinc-finger-proteins (ZNF), 84% of which were shared by at least two groups of tested subjects. Functional analysis of the all DM-CpG detected for the three groups revealed significant networks enriched for neuronal signaling (semaphorin and gustation pathways), estrogen signalling, breast and ovarian cancer signalling or metabolism (sirtuin).

Conclusion: The different methylation profiles of girls in normal and precocious puberty suggest that the dysregulation of the pubertal process in humans is associated with specific epigenetic changes. Our data confirm a role of ZNF genes in pubertal time control. Finally, we suggest that epigenetic control of pubertal onset affects genes involved in signalling pathways that determine the migration and function of GnRH neurons and the occurrence of metabolic and neoplastic diseases that may be associated with CPP in later life.