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Differential DNA methylation in iPSC-derived dopaminergic neurons: a step forward on the role of SNORD116 microdeletion in the pathophysiology of addictive behavior in Prader-Willi syndrome

Molecular Psychiatry (2024)Cite this article

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Abstract

Introduction

A microdeletion including the SNORD116 gene (SNORD116 MD) 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 SNORD116 MD 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 SNORD116 MD 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 SNORD116 MD 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 COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation.

Conclusion

SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance.

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Fig. 1: A heatmap representation of the changes in methylation levels observed in genes related to the dopaminergic synapse pathway observed in SNORD116 MD iPSC-derived neurons differentiated with and without OXT and the changes observed for the same genes in the control iPSC-derived neurons differentiated with and without OXT.
Fig. 2: Display of differential methylation and expression.
Fig. 3: Display of RNA expression in SNORD116 and control iPSC-derived dopaminergic neurons.
Fig. 4: Effect of the SNORD116 deletion on gene expression in dopaminergic neurons differentiated from iPSC.

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Data availability

The RNA sequencing data reported in this article were deposited in the NCBI’s Gene Expression Omnibus (GEO) database: GSE249891.

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Acknowledgements

This work was supported by a grant from the French Association for Prader-Willi Syndrome (grant R15062BB). MGX acknowledges financial support from the France Génomique National infrastructure, funded as part of “Investissement d’Avenir” program managed by the Agence Nationale pour la Recherche (contract ANR-10-INBS-09).

Author information

Authors and Affiliations

  1. Service de psychiatrie d’urgences, de crise et de liaison; Institut des Handicaps Neurologiques, Psychiatriques et Sensoriels, CHU de Toulouse; Infinity Center, Inserm CNRS UMR1291, University of Toulouse 3 Paul Sabatier, Toulouse, France

    Juliette Salles

  2. Endocrine, Bone Diseases and Genetics Unit, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, Paediatric Research Unit, Children’s Hospital, University Hospital; Infinity Center, Inserm CNRS UMR1291, University of Toulouse 3 Paul Sabatier, Toulouse, France

    Sanaa Eddiry & Jean-Pierre Salles

  3. Infinity Center, Inserm CNRS UMR1291, University of Toulouse 3 Paul Sabatier, Toulouse, France

    Saber Amri, Mélissa Galindo & Emmanuelle Lacassagne

  4. MGX-Montpellier GenomiX, Univ. Montpellier, CNRS, Inserm, Montpellier, France

    Simon George & Xavier Mialhe

  5. I2MC - Institut des Maladies Métaboliques et Cardiovasculaires, Inserm, University of Toulouse 3 Paul Sabatier; GeT-Santé, Plateforme Génome et Transcriptome, GenoToul, Toulouse, France

    Émeline Lhuillier

  6. Service d’Addictologie Clinique, Urgences Réanimation Médecine, CHU de Toulouse, Toulouse, France

    Nicolas Franchitto

  7. Institut de Genomique Fonctionnelle, University of Montpellier, Inserm, CNRS, Montpellier, 34090, France

    Freddy Jeanneteau

  8. Infinity Center, Inserm CNRS UMR1291, University of Toulouse 3 Paul Sabatier; Laboratoire de Biochimie – Biologie moléculaire IFB Center CHU Toulouse, Toulouse, France

    Isabelle Gennero

  9. Centre de Référence National du Syndrome de Prader-Willi et Syndromes avec Troubles du Comportement Alimentaire, Unité d’Endocrinologie, Hôpital des Enfants, Institut des Handicaps Neurologiques, Psychiatriques et Sensoriels, CHU de Toulouse; Infinity Center, Inserm CNRS UMR1291, University of Toulouse 3 Paul Sabatier, Toulouse, France

    Maithé Tauber

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Contributions

JS, MT, and JPS developed the initial study design. NF, IG, and FJ provided feedback to improve the design. JS, SA, EL, MG and SE performed the cell culture and RT-qPCR. XA and GS performed DNA methylation and related bioinformatics analysis. EL performed RNA sequencing and related bioinformatic analysis. JS and MT performed the combined statistical analysis. JS, MT, JPS and SE wrote the initial manuscript. All authors contributed to improving the manuscript and responding to the reviewers.

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Correspondence to Juliette Salles.

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Salles, J., Eddiry, S., Amri, S. et al. Differential DNA methylation in iPSC-derived dopaminergic neurons: a step forward on the role of SNORD116 microdeletion in the pathophysiology of addictive behavior in Prader-Willi syndrome. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02542-4

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