Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder.

IF 5.8 1区 医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-10-09 DOI:10.1038/s41398-024-03139-9
Eric Zillich, Hanna Belschner, Diana Avetyan, Diego Andrade-Brito, José Jaime Martínez-Magaña, Josef Frank, Naguib Mechawar, Gustavo Turecki, Judit Cabana-Domínguez, Noèlia Fernàndez-Castillo, Bru Cormand, Janitza L Montalvo-Ortiz, Markus M Nöthen, Anita C Hansson, Marcella Rietschel, Rainer Spanagel, Stephanie H Witt, Lea Zillich
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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.

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人类可卡因使用障碍中 DNA 甲基化和基因表达改变的多组学分析。
大脑结构和功能的变化被认为是可卡因使用障碍(CUD)导致可卡因摄入过多、渴求和复吸的原因。表观遗传和转录变化被假定为 CUD 相关脑部改变的分子基础。在这里,我们利用布罗德曼第 9 区(BA9)的尸检脑组织,通过整合来自同一个体的表观遗传全甲基组(N = 42)和转录组(N = 25)数据,对 CUD 进行了多组学研究。在 N = 1 057 个差异表达基因(p
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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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