MKRN3 methylation abnormalities in patients with pubertal disorders
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Citation
Abstract
Central Precocious Puberty (CPP) is caused by an early maturation of the hypothalamic-pituitary-gonadal (HPG) axis, which results in pulsatile GnRH secretion and gonadal activation before 8 years in girls and 9 years in boys. It is now widely recognized that environmental cues affect the HPG axis and timing of puberty via epigenetic mechanisms, such as DNA methylation. Inactivating mutations in the maternally imprinted, paternally expressed Makorin Ring Finger 3 (MKRN3) gene are the most common genetic defect associated with CPP. However, these mutations represent ~10% of patients with CPP. In genomic imprinting, the expression of one parent allele is “preferred” over the other, and this can occur through differential methylation of CpG islands on the promoter or enhancer region of a gene. These differentially methylated regions (DMRs) are important regulatory regions for the monoallelic expression of imprinted genes. The mechanism that regulates the monoallelic expression of MKRN3 is unknown. The goal of this research was to analyze if methylation changes in the potential DMR 3.7kb upstream of the MRKN3 transcription start site (TSS), the “Islet”, can be associated with disorders of pubertal timing. Site-specific transcription factors can control gene expression by binding to gene promoters and enhancers. It was suggested that the three transcription factor binding sites within this region upstream of MKRN3 may impact the MKRN3 expression patterns that are responsible for CPP through an imprinting mechanism. The use of Targeted Next Generation Sequencing and Pyrosequencing of DNA from whole, peripheral blood allowed for the quantification of the methylation profile of each sample in the Islet region of interest. It was found that the methylation patterns, in a region with many viable transcription factors for MKRN3 expression, presented with hypomethylation in patients with CPP, relative to controls. Also, patients with delayed puberty showed no difference in methylation compared to controls but had hypermethylation of CpG islands compared to CPP cohort. Further research is needed to study the interaction of increased or decreased binding at these transcription factor binding sites and MKRN3 expression.
Description
2024
License
Attribution 4.0 International