H3K4 Trimethylation Mediate Hyperhomocysteinemia Induced Neurodegeneration via Suppressing Histone Acetylation by ANP32A

Homocysteine (Hcy) is an independent and serious risk factor for dementia, including Alzheimer’s disease (AD), but the precise mechanisms are still poorly understood. In the current study, we observed that the permissive histone mark trimethyl histone H3 lysine 4 (H3K4me3) and its methyltransferase KMT2B were significantly elevated in hyperhomocysteinemia (HHcy) rats, with impairment of synaptic plasticity and cognitive function. Further research found that histone methylation inhibited synapse-associated protein expression, by suppressing histone acetylation. Inhibiting H3K4me3 by downregulating KMT2B could effectively restore Hcy-inhibited H3K14ace in N2a cells. Moreover, chromatin immunoprecipitation revealed that Hcy-induced H3K4me3 resulted in ANP32A mRNA and protein overexpression in the hippocampus, which was regulated by increased transcription Factor c-fos and inhibited histone acetylation and synapse-associated protein expression, and downregulating ANP32A could reverse these changes in Hcy-treated N2a cells. Additionally, the knockdown of KMT2B restored histone acetylation and synapse-associated proteins in Hcy-treated primary hippocampal neurons. These data have revealed a novel crosstalk mechanism between KMT2B-H3K4me3-ANP32A-H3K14ace, shedding light on its role in Hcy-related neurogenerative disorders.

We observed that the permissive histone mark H3K4me3 and its methyltransferase KMT2B were significantly elevated in hyperhomocysteinemia (HHcy) rats, with impairment of cognitive function. Further research found that H3K4me3 inhibited synapse associated protein expression, by suppressing ANP32A/H3K14ace. Moreover, siKMT2B restored ANP32A/H3K14ace and synapse-associated proteins in Hcy-treated N2a cells and primary hippocampal neurons. We found a novel crosstalk between KMT2B-H3K4me3-ANP32A-H3K14ace, shedding light on its role in Hcy-related neurogenerative disorders.