Repression of Egr2 target genes by the NuRD complex

Abstract

Early Growth Response (EGR) transactivators act as critical regulators of nervous system development, immune system regulation, and progression of prostate cancer. The NAB1 and NAB2 (NGFI-A/EGR1-binding) transcriptional corepressors directly interact with three EGR family members (Egr1/NGFI-A/zif268, Egr2/Krox20, and Egr3) and repress activation of their target promoters. In work described here, we show that NAB2 interacts with the CHD4 (Chromodomain Helicase DNA-binding protein 4) subunit of the NuRD (Nucleosome Remodeling and Deacetylase) chromatin remodeling complex. In addition, we show that EGR activity is modulated by at least two repression domains within NAB2, one of which uniquely requires interaction with CHD4 (and associated histone deacetylase activity) in order to repress transcription. Both NAB2 and the closely related NAB1 protein can interact with CHD4, and the interaction is regulated by alternative splicing. Furthermore, we show that repression of endogenous Egr2 target genes by NAB2 involves interaction with CHD4. Finally, in vivo chromatin immunoprecipitation reveals that CHD4 is enriched at the promoter templates of these genes. This work was supported by a grant from the National Institutes of Health (HD41590) to JS, and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (P30 HD03352).