Decreased MEF2A Expression Regulated by Its Enhancer Methylation Inhibits Autophagy and May Play an Important Role in the Progression of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles which significantly affects people’s life quality. Recently, AD has been found to be closely related to autophagy. The aim of this study was to identify autophagy-related genes associated with the pathogenesis of AD from multiple types of microarray and sequencing datasets using bioinformatics methods and to investigate their role in the pathogenesis of AD in order to identify novel strategies to prevent and treat AD. Our results showed that the autophagy-related genes were significantly downregulated in AD and correlated with the pathological progression. Furthermore, enrichment analysis showed that these autophagy-related genes were regulated by the transcription factor myocyte enhancer factor 2A (MEF2A), which had been confirmed using si-MEF2A. Moreover, the single-cell sequencing data suggested that MEF2A was highly expressed in microglia. Methylation microarray analysis showed that the methylation level of the enhancer region of MEF2A in AD was significantly increased. In conclusion, our results suggest that AD related to the increased methylation level of MEF2A enhancer reduces the expression of MEF2A and downregulates the expression of autophagy-related genes which are closely associated with AD pathogenesis, thereby inhibiting autophagy.

A map of the spatial distribution and tumour‐associated macrophage states in glioblastoma and grade 4 IDH‐mutant astrocytoma

“…had overactivation of JUN, which is implicated in cytokine production and microglia polarization [36]. Macrophage activation suppressor ETV5 and microglia negative regulator MEF2A in Alzheimer's disease [37,38] were enriched in the Mg‐TAM_hom. cluster (Figure 4A), sustaining the inactive state of Mg‐TAM_hom.…”

“…Delineating TAM diversity in glioma using scRNA-seq 125 Delineating TAM diversity in glioma using scRNA-seq 127 Delineating TAM diversity in glioma using scRNA-seq 129 disease [37,38] were enriched in the Mg-TAM_hom. cluster (Figure 4A), sustaining the inactive state of Mg-TAM_hom.…”

Comprehensive analysis of dysregulated circular RNAs and construction of a ceRNA network involved in the pathology of Alzheimer’s disease in a 5 × FAD mouse model

“…Many target genes of miR-6240 have been proposed to be related to AD etiopathogenesis, including serine and arginine-rich splicing factor 1 ( SRSF1 ), hypoxia-inducible factor-1α ( HIF1α ), mesenchyme homeobox 2 ( MEOX2 ), cAMP-responsive element-binding protein 1 ( CREB1 ), pericentriolar material-1 ( PCM1 ), coiled-coil containing protein kinases ( ROCK2 ), synaptosomal-associated protein 23 ( SNAP23 ), and myocyte enhancer factor 2A ( MEF2A ). These genes are involved in plaque deposition, tau protein biosynthesis, neuronal dysfunction, neuroinflammation, autophagy, and other pathological processes related to AD ( Chakravarthy et al, 2013 ; Soto et al, 2016 ; Muhammad et al, 2019 ; Adeyemi et al, 2021 ; Li et al, 2021 ; Weber and Herskowitz, 2021 ). SRSF1 is a member of the serine/arginine-rich proteins family, which is involved in the process of exon selection and mRNA output and localization.…”

The Role of MEF2 Transcription Factor Family in Neuronal Survival and Degeneration

“…Alzheimer’s disease is also characterized by downregulation of autophagy-related-genes that are regulated by MEF2A. Methylated-microarray analysis performed by Li and colleagues [ 105 ] showed that methylation level of the enhancer region of MEF2A was increased in AD. It can be speculated that the increased methylation reduces the expression of MEF2A and, as a consequence, downregulates autophagy-related genes that are closely linked to AD pathology.…”