Lax Carlos, Mondo Stephen J, Martínez José F, Muszewska Anna, Baumgart Leo A, Pérez-Ruiz José A, Carrillo-Marín Pablo, LaButti Kurt, Lipzen Anna, Zhang Yu, Guo Jie, Ng Vivian, Navarro Eusebio, Pawlowska Teresa E, Grigoriev Igor V, Nicolás Francisco E, Garre Victoriano
Departamento de Genética y Microbiología, Facultad de Biología, Universidad de Murcia, Murcia, Spain.
US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Nat Commun. 2025 Apr 24;16(1):3843. doi: 10.1038/s41467-025-59170-x.
The discovery of N6-methyladenine (6mA) in eukaryotic genomes, typically found in prokaryotic DNA, has revolutionized epigenetics. Here, we show that symmetric 6mA is essential in the early diverging fungus Rhizopus microsporus, as the absence of the MT-A70 complex (MTA1c) responsible for this modification results in a lethal phenotype. 6mA is present in 70% of the genes, correlating with the presence of H3K4me3 and H2A.Z in open euchromatic regions. This modification is found predominantly in nucleosome linker regions, influencing the nucleosome positioning around the transcription start sites of highly expressed genes. Controlled downregulation of MTA1c reduces symmetric 6mA sites affecting nucleosome positioning and histone modifications, leading to altered gene expression, which is likely the cause of the severe phenotypic changes observed. Our study highlights the indispensable role of the DNA 6mA in a multicellular organism and delineates the mechanisms through which this epigenetic mark regulates gene expression in a eukaryotic genome.
真核生物基因组中N6-甲基腺嘌呤（6mA）的发现彻底改变了表观遗传学，这种修饰通常存在于原核生物DNA中。在这里，我们表明，对称6mA在早期分化的真菌小孢根霉中至关重要，因为负责这种修饰的MT-A70复合物（MTA1c）缺失会导致致死表型。70%的基因中存在6mA，这与开放常染色质区域中H3K4me3和H2A.Z的存在相关。这种修饰主要存在于核小体连接区，影响高表达基因转录起始位点周围的核小体定位。MTA1c的可控下调会减少影响核小体定位和组蛋白修饰的对称6mA位点，导致基因表达改变，这可能是观察到严重表型变化的原因。我们的研究强调了DNA 6mA在多细胞生物中的不可或缺的作用，并阐明了这种表观遗传标记在真核生物基因组中调节基因表达的机制。
