N6-methyladenine DNA Demethylase ALKBH1 Regulates Mammalian Axon Regeneration

Abstract

Recent studies have shown that DNA N6-methyladenine (N6-mA) modification is emerging to be a novel and important epigenetic regulator of mammalian gene transcription. Several studies demonstrated DNA N6-mA in human or rodents was regulated by methyltransferase N6AMT1 and demethylase ALKBH1.Moreover, studies in mouse brain or human glioblastoma cells showed that reduced level of N6-mA or higher level of ALKBH1 was correlated with up regulated levels of genes associated with neuronal development. We thus investigated the functional roles of ALKBH1 in sensory axon regeneration. Our results showed that ALKBH1 regulated the level of N6-mA in sensory neurons, and upon peripheral nerve injury ALKBH1 was up regulated in mouse sensory neurons. Functionally, knocking down ALKBH1 in sensory neurons resulted in reduced axon regeneration in vitro and in vivo, which could be rescued by simultaneously knocking down N6AMT1. Moreover, knocking down ALKBH1 led to decreased levels of many neurodevelopment regulatory genes, including neuritin that is well known to enhance axon growth and regeneration. Our study not only revealed a novel physiological function of DNA N6-mA, but also identified a new epigenetic mechanism regulating mammalian axon regeneration.

Epigenetic modifications of DNA and RNA in Alzheimer’s disease

“…These studies provide further evidence that 6mA plays a role in neurodevelopment. ALKBH1 knockdown mice exhibit impaired axon regeneration and the significant downregulation of 5 key neurodevelopment genes: Inhibitor of DNA Binding 1 (Id1), Ephrin A1 (Efna1), Neuritin 1 (Nrn1), Autophagy related 9B (ATG9B), and Complement C1q like 4 (C1QL4), as well as a trend toward downregulation for 14 others genes including APOE ( Li et al, 2021 ). In accordance with these results, a preliminary study suggests that blood leukocyte 6mA levels are significantly lower in AD ( Lv et al, 2022 ).…”

The biological function of demethylase ALKBH1 and its role in human diseases

“…For example, ALKBH1 expression and decreased DNA N 6 -mA levels have been found to be essential for prompt sensory axon regeneration both in vivo and in vitro. ALKBH1 could aid in sensory axon regeneration by decreasing neuronal DNA N 6 -mA levels and consequently increasing the expression of neurodevelopmental genes [ 60 ]. Crucially, a study encompassing biochemical profiling and structural analyses of ALKBH1 offers compelling evidence that ALKBH1 serves as a crucial DNA demethylase, regulating genome N 6 -mA turnover of unpairing regions associated with dynamic chromosome regulation [ 27 ].…”

ALKBH8 contributes to neurological function through oxidative stress regulation

“…However, there have been very few studies on the functions of the ALKBH family in the central nervous system and any possible associations with neurological disorders. ALKBH1 is reported to contribute to axon regeneration ( 15 ) and hippocampus-dependent learning ( 16 ). Alkbh5 deficiency in mice results in profound and deleterious effects on cerebellar development under hypoxic conditions ( 17 ).…”