CHD8, a Novel ATP-dependent Chromatin Remodeling Enzyme.

[摘要] ATP-dependent chromatin remodeling by the CHD family of proteins plays an important role in the regulation of gene transcription.The CHD family can be subdivided into three families; CHD1-2, CHD3-5, and CHD6-9.While the first two subfamilies have been extensively studied, very little is known about the CHD6-9 subfamily.In this study we demonstrate that CHD8 is a nucleosome-stimulated ATPase, capable of remodeling nucleosome structure.In addition, the tandem Chromodomains of CHD8 are capable of directly binding recombinant histones H3 and H4.We also demonstrate that CHD8 interacts directly with the transcriptional regulator β-catenin and that CHD8 is recruited specifically to the promoter regions of several genes responsive to β-catenin.Utilizing shRNA against CHD8, we demonstrate that CHD8 performs a negative role in regulating β-catenin target gene expression.This regulation is evolutionarily conserved as RNAi against kismet, the apparent Drosophila ortholog of CHD8, similarly results in the activation of β-catenin target genes. WDR5, RbBP5, and Ash2L are core components of the MLL1 WDR5 methyltransferase complex which alters chromatin structure through the covalent modification of histones.MLL1, the catalytic subunit of the complex, catalyzes the methylation of histone H3 lysine 4, a hallmark of active chromatin.We demonstrate that CHD8 exists in a multisubunit complex with WDR5, RbBP5, and Ash2L that may also contain MLL1.Both WDR5 and MLL1 have previously been reported to regulate the expression of Hox genes, a family of genes involved in development.We demonstrate that CHD8 is recruited specifically to the promoter regions of several genes within the HoxA locus.Utilizing shRNA against CHD8, we demonstrate that CHD8 performs a negative role in regulating Hox gene expression.We show that CHD8, like WDR5 and MLL1, regulates Hox gene expression.Taken together, these results demonstrate that CHD8 functions in the transcriptional regulation of both β-catenin target genes and Hox genes and suggest that this regulation is through the ATP-dependent modulation of chromatin structure within the 5’ promoter regions of these genes.Our results suggest that through regulating the expression of β-catenin target genes and Hox genes CHD8 may play a role in both tumorogenesis and development respectively.

[发布机构] University of Michigan

[效力级别] CHD8

[关键词] Chromatin Remodeling;CHD8;Cancer and Development;Chromodomain;Biological Chemistry;Molecular;Cellular and Developmental Biology;Science (General);Science;Cellular & Molecular Biology