Allele-specific non-CG DNA methylation marks domains of active chromatin in female mouse brain

Abstract

DNA methylation at gene promoters in a CG context is associated with transcriptional repression, including at genes silenced on the inactive X chromosome in females. Non-CG methylation (mCH) is a distinct feature of the neuronal epigenome that is differentially distributed between males and females on the X chromosome. However, little is known about differences in mCH on the active (Xa) and inactive (Xi) X chromosomes because stochastic X-chromosome inactivation (XCI) confounds allele-specific epigenomic profiling. We used whole-genome bisulfite sequencing in a mouse model with nonrandom XCI to examine allele-specific DNA methylation in frontal cortex. Xi was largely devoid of mCH, whereas Xa contained abundant mCH similar to the male X chromosome and the autosomes. In contrast to the repressive association of DNA methylation at CG dinucleotides (mCG), mCH accumulates on Xi in domains with transcriptional activity, including the bodies of most genes that escape XCI and at the X-inactivation center, validating this epigenetic mark as a signature of transcriptional activity. Escape genes showing CH hypermethylation were the only genes with CG-hypomethylated promoters on Xi, a well-known mark of active transcription. Finally, we found extensive allele-specific mCH and mCG at autosomal imprinted regions, some with a negative correlation between methylation in the two contexts, further supporting their distinct functions. Our findings show that neuronal mCH functions independently of mCG and is a highly dynamic epigenomic correlate of allelespecific gene regulation.DNA methylation | X-chromosome inactivation | imprinting | Non-CG | Bcor

Analyzing whole genome bisulfite sequencing data from highly divergent genotypes

“…Variants of this strategy are indeed commonly used in analysis, i.e. with alignment to approximate personal genomes; this has been done both in plants (Pignatta et al, 2014;Hagmann et al, 2015;Kawakatsu et al, 2016) and mammals (Schultz et al, 2015;Keown et al, 2017). However, while both the problem and the optimal solution are recognized, the magnitude of the bias is not well understood or described.…”

Loss of Dnmt3a dependent methylation in inhibitory neurons impairs neural function through a mechanism that impacts Rett syndrome

“…Today many features of the classic model for gene regulation by DNA methylation have proven more complex. Rather than static and solely repressive to gene expression, DNA methylation is functionally dynamic (4), and in some cases has been shown to activate gene expression (5)(6)(7)(8) highlighting that context and protein factors that recognize methylated cytosine can alter the transcriptional outcome of this epigenetic mark.…”

UHRF1-SRA recognizes symmetric non-CG methylated DNA through dual-flip out of 5-methyl cytosines

“…Presence of mCH in myocytes is a proof for non-CG methylation in somatic cells (Schultz et al 2015). mCH is a distinct feature of neuronal epigenome that is differentially distributed on X chromosome in males and females (Keown et al 2017;Mo et al 2015). In addition, millions of CA and CT non-CG methylations accumulate during postnatal brain development in mice (Lister et al 2013;Xie et al 2012)and it correlates with reduced gene expression and inactivation of distal regulatory elements in a highly cell type-specific manner (Mo et al 2015).…”

“…In addition, millions of CA and CT non-CG methylations accumulate during postnatal brain development in mice (Lister et al 2013;Xie et al 2012)and it correlates with reduced gene expression and inactivation of distal regulatory elements in a highly cell type-specific manner (Mo et al 2015). A recent study has shown that functioning of mCH in neuron is independent of mCG, and dynamic nature of mCH is correlated with allele specific gene regulation (Keown et al 2017). Fully-mCHG (5′-mCHG-3′/3′-GNmC-5′: where 'H' is A, T or C and 'N' is T, A or G), asymmetric non-CG methylation, is highly prevalent in plants.…”