Roy Bhaskar, Dwivedi Yogesh
Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Neuropsychopharmacology. 2025 Jul 10. doi: 10.1038/s41386-025-02165-5.
Major depressive disorder (MDD) is the most prevalent psychiatric disorder. MDD patients are at substantially increased risk of dying by suicide. The molecular mechanisms associated with MDD and associated suicide are not clearly understood, which impedes the development of novel therapeutics. N6-methyladenosine (m6A) is the most prevalent epitranscriptomic mark on mRNA and plays significant roles in various physiological processes. This study investigated m6A RNA methylation and its potential contributions to MDD pathogenesis and associated suicide risk. High-throughput microarray analysis in the dorsolateral prefrontal cortex (dlPFC) of MDD subjects (n = 49) and non-psychiatric controls (n = 49) identified 1290 significantly hypermethylated and 6842 hypomethylated transcripts, with most m6A sites enriched in coding sequences. Chromosome-wide analysis showed hypermethylation hotspots on chromosomes 1 and 19. In-silico analysis identified enriched AAGA and ACCCA m6A motifs in the MDD group. Expression analysis revealed reduced FTO demethylase and increased METTL3 methyltransferase levels. A majority of M6A hypermethylated genes showed inverse correlation with their expression levels. Functional enrichment of hypermethylated genes highlighted disruptions in molecular pathways relevant to MDD. Comparison of MDD-non-suicide (n = 32) and MDD-suicide (n = 17) identified 6750 transcripts with significant hypermethylation, whereas 6159 transcripts had significant hypomethylation in the MDD-suicide group; of them, 196 hypermethylated genes were explicitly associated with suicide in the MDD group, whereas 38 hypermethylated genes appeared to elevate suicide risk in MDD patients. Also, the MDD-suicide group had distinct neuromolecular pathways associated with these risk genes. Collectively, the findings suggest a critical role for m6A methylation in modulating the molecular networks underlying MDD and suicide susceptibility.
重度抑郁症（MDD）是最常见的精神疾病。MDD患者自杀死亡风险大幅增加。与MDD及相关自杀行为相关的分子机制尚不清楚，这阻碍了新型疗法的开发。N6-甲基腺苷（m6A）是mRNA上最常见的表观转录组标记，在各种生理过程中发挥重要作用。本研究调查了m6A RNA甲基化及其对MDD发病机制和相关自杀风险的潜在影响。对MDD受试者（n = 49）和非精神疾病对照者（n = 49）的背外侧前额叶皮质（dlPFC）进行高通量微阵列分析，确定了1290个显著高甲基化转录本和6842个低甲基化转录本，大多数m6A位点富集于编码序列中。全染色体分析显示1号和19号染色体上存在高甲基化热点。生物信息学分析确定MDD组中富集AAGA和ACCCA m6A基序。表达分析显示FTO去甲基酶水平降低，METTL3甲基转移酶水平升高。大多数m6A高甲基化基因与其表达水平呈负相关。高甲基化基因的功能富集突出了与MDD相关的分子途径的破坏。比较MDD非自杀组（n = 32）和MDD自杀组（n = 17）发现，MDD自杀组中有6750个转录本显著高甲基化，而6159个转录本显著低甲基化；其中，196个高甲基化基因与MDD组中的自杀行为明确相关，而38个高甲基化基因似乎增加了MDD患者的自杀风险。此外，MDD自杀组有与这些风险基因相关的独特神经分子途径。总体而言，这些发现表明m6A甲基化在调节MDD和自杀易感性的分子网络中起关键作用。
