Journal Article

Elevated EGR1 binding at enhancers in excitatory neurons correlates with neuronal subtype-specific epigenetic regulation

Xu, Xiguang, Xie, Hehuang, Carrillo, Gabriela L., Fox, Michael A., Yin, Liduo, Lin, Yu, Cun, Yupeng, Conacher, Benjamin, Lu, Xuemei

2025

Overview

Background Brain development and neuronal cell specification are accompanied by epigenetic changes that enable the regulation of diverse gene expression patterns. During these processes, transcription factors interact with cell-type-specific epigenetic marks, binding to unique sets of cis-regulatory elements in different cell types. However, the detailed mechanisms through which cell-type-specific gene regulation is established in neurons remain to be explored. Results In this study, we conducted a comparative histone modification analysis between excitatory and inhibitory neurons. Our results revealed that neuronal cell-type-specific histone modifications are enriched in super enhancer regions that contain abundant EGR1 motifs. Further CUT&RUN assay confirmed that excitatory neurons exhibit more EGR1 binding sites, primarily located in enhancers. Integrative analysis demonstrated that EGR1 binding is strongly correlated with various epigenetic markers of open chromatin regions and is linked to distinct gene pathways specific to neuronal subtypes. In inhibitory neurons, most genomic regions containing EGR1 binding sites become accessible during early embryonic stages, whereas super enhancers in excitatory neurons, which also host EGR1 binding sites, gain accessibility during postnatal stages. Conclusions This study highlights the crucial role of transcription factor binding, such as EGR1, to enhancer regions, which may be key to establishing cell-type-specific gene regulation in neurons.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Accessibility / Animals / Anopheles / Binding Sites / Biomedical and Life Sciences / Brain / Chromatin / Comparative analysis / DNA binding proteins / DNA methylation / Early Growth Response Protein 1 - genetics / Early Growth Response Protein 1 - metabolism / EGR-1 protein / EGR1 / Enhancer / Enhancer Elements, Genetic / Enhancers / Epigenesis, Genetic / Epigenetic / Epigenetic inheritance / Epigenetics / Excitatory neuron / Gene expression / Gene regulation / Genes / Genetic aspects / Genetic regulation / Genomes / Histones / Inhibitory neuron / Life Sciences / Mice / Neurological research / Neurons / Neurons - metabolism / Neurophysiology / Protein binding / Regulatory sequences / Transcription factor / Transcription factors