| Autor: |
Salles, Juliette, Eddiry, Sanaa, Amri, Saber, Galindo, Mélissa, Lacassagne, Emmanuelle, George, Simon, Mialhe, Xavier, Lhuillier, Émeline, Franchitto, Nicolas, Jeanneteau, Freddy, Gennero, Isabelle, Salles, Jean-Pierre, Tauber, Maithé |
| Zdroj: |
Molecular Psychiatry; September 2024, Vol. 29 Issue: 9 p2742-2752, 11p |
| Abstrakt: |
Introduction: A microdeletion including the SNORD116gene (SNORD116MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons. Methods: We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT. Results: The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMTand SLC6A3. COMTdisplayed hypermethylation and under-expression in SNORD116MD, and SLC6A3displayed hypomethylation and over-expression in SNORD116MD. RT-qPCR confirmed significant over-expression of SLC6A3in SNORD116 MDneurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation. Conclusion: SNORD116MD dopaminergic neurons displayed differential methylation and expression in the COMTand SLC6A3genes, which are related to dopaminergic clearance. |
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