Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder
Zillich, Eric (Heidelberg University)
Belschner, Hanna (Heidelberg University (Mannheim, Alemanya))
Avetyan, Diana (Heidelberg University (Mannheim, Alemanya))
Andrade-Brito, Diego (Heidelberg University (Mannheim, Alemanya))
Martínez-Magaña, José Jaime (Yale University School of Medicine)
Frank, Josef (Heidelberg University (Mannheim, Alemanya))
Mechawar, Naguib (McGill University. Department of Psychiatry)
Turecki, Gustavo (McGill University. Department of Psychiatry)
Cabana-Domínguez, Judit (Vall d'Hebron Institut de Recerca (VHIR))
Fernàndez-Castillo, Noèlia (Universitat de Barcelona)
Cormand, Bru (Universitat de Barcelona)
Montalvo-Ortiz, Janitza L. (Yale University School of Medicine)
Nöthen, Markus M. (University of Bonn)
Hansson, Anita C. (Heidelberg University)
Rietschel, Marcella (Heidelberg University)
Spanagel, Rainer (Heidelberg University)
Witt, Stephanie H. (Heidelberg University)
Zillich, Lea (Heidelberg University)

Date:	2024
Abstract:	Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0. 05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0. 05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.
Grants:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01093 Fundació la Marató de TV3 202218-3
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Epigenetics and plasticity ; Addiction
Published in:	Translational psychiatry, Vol. 14 (october 2024) , ISSN 2158-3188

DOI: 10.1038/s41398-024-03139-9
PMID: 39384764

14 p, 8.4 MB

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