Non-CG DNA methylation and MeCP2 stabilize repeated tuning of long genes that distinguish closely related neuron types.

The extraordinary diversity of neuron types in the mammalian brain is delineated at the highest resolution by subtle gene expression differences that may require specialized molecular mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and utilize neuron-enriched non-CG DNA methylation (mCA) together with the Rett syndrome protein, MeCP2, to control gene expression, but the function of these unique gene structures and machinery in regulating finely resolved neuron type-specific gene programs has not been explored. Here, we employ epigenomic and spatial transcriptomic analyses to discover a major role for mCA and MeCP2 in maintaining neuron type-specific gene programs at the finest scale of cellular resolution.

NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons.

During postnatal development, the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This methylation is critical for transcriptional regulation, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). Here, we show in mice that genome topology and gene expression converge to shape histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation.

NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons.

Unlabelled: During postnatal development the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This unique methylation is critical for transcriptional regulation in the mature mammalian brain, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). The mechanisms determining genomic non-CG methylation profiles are not well defined however, and it is unknown if this pathway is disrupted in additional NDDs.

DNMT3A Haploinsufficiency Results in Behavioral Deficits and Global Epigenomic Dysregulation Shared across Neurodevelopmental Disorders.

Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here, we define the effects of DNMT3A mutations associated with neurodevelopmental disease. We show that diverse mutations affect different aspects of protein activity but lead to shared deficiencies in neuronal DNA methylation.

Emerging Insights into the Distinctive Neuronal Methylome.

The genomes of mammalian neurons are enriched for unique forms of DNA methylation, including exceptionally high levels of non-CG methylation. Here, we review recent studies defining how non-CG methylation accumulates in neurons and is read out by the critical regulator of neuronal transcription, MeCP2. We discuss the role of gene expression and genome architecture in establishing non-CG methylation and highlight emerging mechanistic insights into how non-CG methylation and MeCP2 control transcription.

MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation.

The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here, we find that genes repressed by MeCP2 are often located within megabase-scale regions of high non-CG methylation that correspond with topologically associating domains of chromatin folding.

Comprehensive DNA methylation analysis of hepatitis B virus genome in infected liver tissues.

Hepatitis B virus (HBV) is a hepatotropic virus causing hepatitis, cirrhosis and hepatocellular carcinoma (HCC). The methylation status of the HBV DNA in its different forms can potentially provide insight into the pathogenesis of HBV-related liver diseases, including HCC, however this is unclear. The goal of this study is to obtain comprehensive DNA methylation profiles of the three putative CpG islands in the HBV DNA in infected livers, with respect to liver disease progression.

The Theobroma cacao B3 domain transcription factor TcLEC2 plays a duel role in control of embryo development and maturation.

Background: The Arabidopsis thaliana LEC2 gene encodes a B3 domain transcription factor, which plays critical roles during both zygotic and somatic embryogenesis. LEC2 exerts significant impacts on determining embryogenic potential and various metabolic processes through a complicated genetic regulatory network.

Results: An ortholog of the Arabidopsis Leafy Cotyledon 2 gene (AtLEC2) was characterized in Theobroma cacao (TcLEC2).