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EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity

Zhixiong Sun,Xiguang Xu,Jianlin He,Alexander Murray,Ming-an Sun,Xiaoran Wei,Xia Wang,E. McCoig,Evan Xie,Xi Jiang,Liwu Li,Jinsong Zhu,Jianjun Chen,Alexei Morozov,Alicia M. Pickrell,M. Theus,Hehuang Xie

Published 2019 in Nature Communications

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. It is unclear why neuronal activity induced methylation changes are limited to specific loci in the genome. Here, authors show that the DNA demethylation enzyme, TET1, gains its specificity via the interaction with EGR1, a sequence specific DNA binding protein.

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