Abstract
How epigenetic information is propagated during somatic cell divisions is still unclear but is absolutely critical for preserving gene expression patterns and cellular identity. Here we show an unanticipated mechanism for inheritance of DNA methylation patterns where the epigenetic mark not only recruits the catalyzing enzyme but also regulates the protein level, i.e. the enzymatic product (5-methylcytosine) determines the level of the methylase, thus forming a novel homeostatic inheritance system. Nucleosomes containing methylated DNA stabilize de novo DNA methyltransferases, DNMT3A/3B, allowing little free DNMT3A/3B enzymes to exist in the nucleus. Stabilization of DNMT3A/3B on nucleosomes in methylated regions further promotes propagation of DNA methylation. However, reduction of cellular DNA methylation levels creating more potential CpG substrates counter-intuitively results in a dramatic decrease of DNMT3A/3B proteins due to diminished nucleosome binding and subsequent degradation of the unstable free proteins. These data show an unexpected self-regulatory inheritance mechanism that not only ensures somatic propagation of methylated states by DNMT1 and DNMT3A/3B enzymes but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes.
Highlights
DNA methylation is a stable gene silencing mechanism required for key biological processes including embryogenesis, genomic imprinting, X-chromosome inactivation, repression of transposons and maintenance of tissue specific gene expression patterns [1,2]
Recent studies suggest that DNMT1 alone cannot ensure proper maintenance of methylation patterns [7] and requires co-operative activity of the de novo DNMT3A/3B enzymes [8,9,10], which are ubiquitously expressed in somatic cells
Proper inheritance of DNA methylation patterns is essential for preserving cellular identity and preventing malignant cellular transformation
Summary
DNA methylation is a stable gene silencing mechanism required for key biological processes including embryogenesis, genomic imprinting, X-chromosome inactivation, repression of transposons and maintenance of tissue specific gene expression patterns [1,2]. Proper maintenance of DNA methylation patterns is essential for preserving cellular identity and preventing malignant cellular transformation. Recent studies suggest that DNMT1 alone cannot ensure proper maintenance of methylation patterns [7] and requires co-operative activity of the de novo DNMT3A/3B enzymes [8,9,10], which are ubiquitously expressed in somatic cells. A revised model of inheritance was recently proposed assigning DNMT3A/3B to a maintenance role in somatic cells [11]; questions still remain regarding the molecular mechanisms guiding the maintenance activity of these de novo enzymes
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