The methyltransferase N6amt1 regulates hippocampal neurogenesis through 6 mA modification of Txnrd3 DNA - Abstract and study summary

Sep 30, 2026

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N6-methyladenine (6 mA) is the dominant DNA modification in mammals and other eukaryotes, yet its function in adult hippocampal neurogenesis is unclear. This study demonstrates that the methyltransferase N6amt1 and 6 mA are highly enriched in hippocampal neurons in vitro and in vivo. N6amt1 knockdown lowers 6 mA, neuronal genesis, and proliferation while driving glial differentiation; conversely, overexpression enhances neuronal differentiation and proliferation. Mechanistically, N6amt1-dependent 6 mA on Txnrd3 DNA increases Txnrd3 transcription and restores defects caused by N6amt1 loss. N6amt1 deficiency impairs neurogenesis and spatial memory in adult mice, suggesting N6amt1 as a therapeutic target for cognitive impairment.

LanguageEnglish

CategoryResearch & Report

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Pages14

Reading Time35 min

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Introduction

Materials and methods

Cell culture and transfection

Cellular and Molecular Life Sciences (2026) 83:24 [https://doi.org/10.1007/s00018-025-06008-w](https://doi.org/10.1007/s00018-025-06008-w) Cellular and Molecular Life Sciences ORIGINAL ARTICLE The methyltransferase N6amt1 regulates hippocampal neurogenesis through 6 mA modification ofTxnrd3 DNA Yuanfei Wu1 · Wenhui Ma1 · Qingqing Li1,2 · Yang Li1 · Linjie Xie1 · Xuejian Kong3 · Shuwei Chen1 · Qian Wang1 · Aiguo Xuan1,3,4 Received: 21 June 2025 / Revised: 28 October 2025 / Accepted: 26 November 2025 © The Author(s) 2025 Abstract N6-methyladenine (6 mA), the most prevalent DNA modification in mammals and other eukaryotes, regulates DNA mismatch repair, chromosome replication, and transcription. However, its role in adult hippocampal neurogenesis remainsunkown. Here we showed that the methyltransferase N6amt1 and 6 mA modification were highly enriched in hippocampal neurons both in vitro and in vivo. Functionally, knockdown of N6amt1 in neural stem cells (NSCs) significantly reduced 6 mA levels, neuronal genesis, and proliferation while promoting glial differentiation. Conversely, N6amt1 overexpression enhanced neuronal differentiation and proliferation. Mechanistically, N6amt1-mediated 6 mA modification ofTxnrd3 DNA increased its transcription, thereby promoting hippocampal neurogenesis. Furthermore, exogenous Txnrd3 overexpression rescued the defects in cell differentiation and proliferation induced by N6amt1 depletion. Notably, N6amt1 deficiency impaired hippocampal neurogenesis and spatial memory in adult mice. Our findings highlight the critical role of DNA 6 mA in N6amt1-mediated neurogenesis and suggest that targeting N6amt1 may offer a novel therapeutic strategy for neurological disorders associated with cognitive impairment. Keywords Neurogenesis · Learning and memory · N6-methyladenine · N6amt1 · Txnrd3 Introduction Adult hippocampal neurogenesis (AHN) persists throughout life in mammals and is critical for learning and memory functions [1] . Studies in rodent models of neurodegenerative Yuanfei Wu, Wenhui Ma and Qingqing Li contributed equally to this work. 􀀍 Aiguo Xuan [xag2005@163.com](xag2005@163.com) 1 Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, School of Basic Medical Sciences, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 2 The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China 3 The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China 4 Scientific Research Center of Guangzhou Medical University, Guangzhou, China diseases advance the possibility that targeting neurogenesis may ameliorate cognitive deficits [2, 3] . However, the regulatory mechanism of AHN is extremely complex, and it is finely modulated by intrinsic and extrinsic factors including genetics, epigenetics, environmental cues, and brain’s microenvironment [4, 5]. Therefore, digging into the molecular mechanisms underlying AHN are required for finding therapeutic target of AHN-related cognitive impairment. 6 mA modification is extensively distributed across the genome and significantly enriched in exonic regions in vertebrates and mammalian cells [6] . Dynamic regulation of DNA 6 mA catalyzed by the methyltransferases N6amt1/ Mettl4 and the demethylases Alkbh4/Alkbh1 elaborately modulate the gene and transposon expression including activation and suppression, and is associated with various human diseases and biological processes such as tumorigenesis, stress response, and cell differentiation [7] . Enhancing genomic DNA 6 mA levels by overexpression of N6amt1 or silencing ofAlkbh1 inhibit tumorigenesis and metastasis [8–10] . 6 mA modified genes associated with neuropsychiatric disorders are dynamically regulated in the mouse brain following environmental stress response and mitochondrial 1

FAQs

What role does N6amt1 play in adult hippocampal neurogenesis?

The study shows that N6amt1 and 6 mA are enriched in hippocampal neurons and that altering N6amt1 levels changes neurogenesis outcomes in vitro and in vivo.

How does N6amt1 affect neural stem cells and cell fate?

N6amt1 knockdown reduces 6 mA levels, neuronal genesis, and proliferation and promotes glial differentiation, while N6amt1 overexpression enhances neuronal differentiation and proliferation.

What mechanism links N6amt1 to neurogenesis and cognitive behavior?

N6amt1-mediated 6 mA modification of Txnrd3 DNA increases Txnrd3 transcription; Txnrd3 overexpression rescues differentiation and proliferation defects caused by N6amt1 depletion, and N6amt1 deficiency impairs neurogenesis and spatial memory in adult mice.

Sep 30, 2026

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