Locus-specific DNA methylation of Mecp2 promoter leads to autism-like phenotypes in mice

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disease with a strong heritability, but recent evidence suggests that epigenetic dysregulation may also contribute to the pathogenesis of ASD. Especially, increased methylation at the MECP2 promoter and decreased MECP2 expression were observed in the brains of ASD patients. However, the causative relationship of MECP2 promoter methylation and ASD has not been established. In this study, we achieved locus-specific methylation at the transcription start site (TSS) of Mecp2 in Neuro-2a cells and in mice, using nuclease-deactivated Cas9 (dCas9) fused with DNA methyltransferase catalytic domains, together with five locus-targeting sgRNAs. This locus-specific epigenetic modification led to a reduced Mecp2 expression and a series of behavioral alterations in mice, including reduced social interaction, increased grooming, enhanced anxiety/depression, and poor performance in memory tasks. We further found that specifically increasing the Mecp2 promoter methylation in the hippocampus was sufficient to induce most of the behavioral changes. Our finding therefore demonstrated for the first time the casual relationship between locus-specific DNA methylation and diseases symptoms in vivo, warranting potential therapeutic application of epigenetic editing.

Prenatal and postnatal traffic pollution exposure, DNA methylation in Shank3 and MeCP2 promoter regions, H3K4me3 and H3K27me3 and sociability in rats’ offspring

“…We found both male and female offspring under early-life exposure had marked higher levels of methylation at the MeCP2 promoter and the less content of MeCP2 when compared with those under exposure during full gestation, which implied postnatal time was a sensitive window for perturbations of methylation. The same result was also observed in the frontal cortex of ASD patients and in the mice that was modified on at the ~ 500-bp TSS region of MeCP2 with a range of behavioral alterations, such as reduced social interaction [ 21 , 36 ]. In the prenatal period, MeCP2 acts on ADAM10/NOTCH signaling via miR-197 to disrupt the differentiation of neural progenitor cells into neurons [ 37 ].…”

Substantial acetylcholine reduction in multiple brain regions of Mecp2-deficient female rats and associated behavioral abnormalities

“…We first analyzed the effect of Mecp2 gene deficiency on rat social behaviors at 8, 12, and 23 w. The frequency and duration of contact behaviors gradually increased with age among female Mecp2 +/+ rats but gradually declined with age among female Mecp2 +/− rats, and both parameters were significantly lower compared to female Mecp2 +/+ rats by 23 w ( Fig 2A and 2B ). We next analyzed self-grooming behavior during the social interaction test as higher frequency and longer duration are considered endophenotypic hyper-repetitive behaviors of autism spectrum disorder [ 21 – 23 ] and male Mecp2 mutant mice [ 24 – 26 ]. The frequencies ( Fig 3A ) of self-grooming were significantly reduced and the duration ( Fig 3B ) tended to be reduced but not significant in female Mecp2 +/− rats.…”

The Metallome as a Link Between the “Omes” in Autism Spectrum Disorders

“…Various ASD-associated genes and receptors have been identified as the target of epigenetic alterations, such as SHANK3, MECP2, FMR1, etc. (Edamura and Pearson, 2005;Zhu et al, 2014;Yuksel et al, 2016;Lu et al, 2020). A histone acetylomewide association study published in 2016 carried out ChIPsequencing on 257 postmortem samples from individuals with ASD along with matched controls indicated that approximately 68% of ASD cases contained a mutual acetylome signature.…”