Dataset Information

The NuRD architecture.

ABSTRACT: The nucleosome remodeling and deacetylase (NuRD) complex regulates chromatin organization, gene transcription, genomic stability and developmental signaling. NuRD has a unique dual enzymatic activity, containing an ATPase and a histone deacetylase among its six core subunits. Recent studies indicate that NuRD composition and the interplay between subunits may dictate the diverse functions of the complex. In this review, we examine the structures and biological roles of the NuRD subunits and discuss new avenues of research to advance our understanding of the NuRD-mediated signaling network.

SUBMITTER: Allen HF

PROVIDER: S-EPMC3652912 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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The NuRD architecture.

Allen Hillary F HF Wade Paul A PA Kutateladze Tatiana G TG

Cellular and molecular life sciences : CMLS 20130123 19

The nucleosome remodeling and deacetylase (NuRD) complex regulates chromatin organization, gene transcription, genomic stability and developmental signaling. NuRD has a unique dual enzymatic activity, containing an ATPase and a histone deacetylase among its six core subunits. Recent studies indicate that NuRD composition and the interplay between subunits may dictate the diverse functions of the complex. In this review, we examine the structures and biological roles of the NuRD subunits and disc ...[more]

PMID: 23340908

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Project description:As high fetal hemoglobin levels ameliorate the underlying pathophysiological defects in sickle cell anemia and beta (β)-thalassemia, understanding the mechanisms that enforce silencing of fetal hemoglobin postnatally offers the promise of effective molecular therapy. Depletion of the Nucleosome Remodeling and Deacetylase complex member MBD2 causes a 10-20-fold increase in γ-globin gene expression in adult β-globin locus yeast artificial chromosome transgenic mice. To determine the effect of MBD2 depletion in human erythroid cells, genome editing technology was utilized to knockout MBD2 in Human Umbilical cord Derived Erythroid Progenitor-2 cells resulting in γ/γ+β mRNA levels of approximately 50% and approximately 40% fetal hemoglobin by high performance liquid chromatography. In contrast, MBD3 knockout had no appreciable effect on γ-globin expression. Knockdown of MBD2 in primary adult erythroid cells consistently increased γ/γ+β mRNA ratios by approximately 10-fold resulting in approximately 30-40% γ/γ+β mRNA levels and a corresponding increase in γ-globin protein. MBD2 exerts its repressive effects through recruitment of the chromatin remodeler CHD4 via a coiled-coil domain, and the histone deacetylase core complex via an intrinsically disordered region. Enforced expression of wild-type MBD2 in MBD2 knockout cells caused a 5-fold decrease in γ-globin mRNA while neither the coiled-coil mutant nor the intrinsically disordered region mutant MBD2 proteins had an inhibitory effect. Co-immunoprecipitation assays showed that the coiled-coil and intrinsically disorder region mutations disrupt complex formation by dissociating the CHD4 and the histone deacetylase core complex components, respectively. These results establish the MBD2 Nucleosome Remodeling and Deacetylase complex as a major silencer of fetal hemoglobin in human erythroid cells and point to the coiled-coil and intrinsically disordered region of MBD2 as potential therapeutic targets.

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The NuRD architecture.

Publications

The NuRD architecture.

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