Leaving a Lasting Mark

RESEARCH HIGHLIGHTS

Nature Reviews Neuroscience | Published online 09 Nov 2017; doi:10.1038/nrn.2017.144

y tt e /G ko n e h c EPIGENETICS d

u r Leaving a lasting mark

Epigenetic modifications may under- age, and the analysis of mice in which transcription of the genes on which lie the influence of early life experi- Dnmt3a was disrupted in the brain the mark is found. The effects of DNA ences on neuronal development and (Dnmt3a conditional knockout (cKO) methylation on gene expression are function, yet the molecular mecha- mice) confirmed the importance thought to be mediated through the nisms involved are poorly understood. of DNMT3A in establishing mCA recruitment of a repressive complex Greenberg and colleagues show that deposition. that includes methyl-CpG-binding in mice, methylation at CA sequences During early postnatal life, neu- protein 2 (MECP2). Here, the authors (mCA) in neuronal genes is modified ronal activity associated with sensory showed that MECP2 binding across by early postnatal experience, provid- experience alters neuronal gene the neuronal genome was correlated ing a mechanism to fine-tune gene expression. The authors showed that with the pattern of mCA deposition. expression in the adult. mice in which activity-dependent Mice in which Mecp2 was disrupted Unusually high levels of mCA are gene expression was boosted by exhibited changes in gene expression found in neurons, which suggests that treatment with kainic acid or that mirrored those of Dnmt3a cKO it is important for neuronal function. through mutation of a transcriptional mice, supporting the role of this To examine the nature of neuronal repressor gene exhibited decreased protein in mCA-driven tuning of gene alterations CA sequence methylation, the authors DNMT3A binding to, and mCA expression. in activity- performed chromatin immunoprecip- deposition at, activity-regulated This study outlines a mechanism itation followed by sequencing, using genes. Dnmt3a cKO mice exhibited through which early-life influences dependent an antibody for DNA methyltrans- no changes in the expression levels of that drive activity-dependent gene gene ferase 3A (DNMT3A, the enzyme activity-dependent genes, indicating expression can translate into the expression that mediates mCA deposition), on that alterations in activity-dependent lasting restraint of the expression extracts of the developing mouse cor- gene expression drive (rather than of particular genes throughout the drive... tex and hippocampus. They observed follow) alterations in DNMT3A lifetime of a neuron. These results alterations a transient recruitment of DNMT3A binding and mCA deposition. may also provide insight into disor- in DNMT3A to the neuronal genome at 2 weeks of What is the function of activity- ders caused by loss of DNMT3A or binding age and showed that it preferentially regulated mCA deposition? The MECP2 function. binds to neuronal genes expressed at authors showed that in Dnmt3a Katherine Whalley and mCA low but detectable levels. This pattern cKO mice, the loss of mCA at genes ORIGINAL ARTICLE Stroud H. et al. Early-life deposition of DNMT3A recruitment corre- normally expressed at low levels gene expression in neurons modulates lasting sponded to stable patterns of mCA modestly increased their expression, epigenetic states. Cell http://doi.org/10.1016/j. cell.2017.09.047 (2017) deposition observed at 8 weeks of suggesting that mCA constrains the