Abstract
Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.
Highlights
Life experience can leave lasting marks, such as epigenetic changes, in the brain
Using HOMER30, we determined the motifs for transcription factors (TFs) enriched in each co-methylated module (Supplementary Fig. 1c, 1f and Supplementary Data 1) and identified Egr[1] is associated with module I, the largest module for both human and mouse
The CpG dinucleotides within the EGR1 binding motifs are gradually demethylated during postnatal brain development and the methylation losses are limited in neurons (Supplementary Fig. 2)
Summary
Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. It has been well acknowledged that early postnatal experience is critical for brain development and may induce long-lasting epigenetic changes in postmitotic neurons[1,2]. Neuronal activity-induced DNA methylation changes may occur within hours after electroconvulsive stimulation[18] This suggests that neurons can react to environmental stimuli and guide the epigenetic machinery to desired genomic loci swiftly. A seminal study has established a link between maternal care and methylation programming during early postnatal brain development, and Egr[1] was proposed to be an epigenetic regulator of glucocorticoid receptor[1]. We explored the epigenetic regulatory mechanism underlying the birth of bipolar methylated loci and identified EGR1 as a key mediator involved in brain epigenome programming during postnatal development. Our results implicate the interaction between transcription factors (TFs) and epigenetic machinery as a general mechanism to achieve locus-specific epigenetic regulation upon neuronal activation
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