Abstract
Dynamic changes in chromatin structure through ATP-dependent remodeling and covalent modifications on histones play important roles in transcription regulation. Among the many chromatin modifiers identified, the NuRD (nucleosome remodeling histone deacetylase) complex is unique because it possesses both nucleosome remodeling and histone deacetylase activities. To understand the biological function of the NuRD complex, we generated a knock-out mouse model of the Mta2 (metastasis-associated protein 2) gene, which encodes a NuRD-specific component. Mta2 null mice exhibited partial embryonic lethality. The surviving mice developed lupus-like autoimmune symptoms including skin lesions, bodyweight loss, glomerulonephritis, liver inflammation, and production of autoantibodies. Transplantation of bone marrow cells from Mta2 null mice recapitulated some of the symptoms including skin lesion and bodyweight loss in the recipient mice. Mta2 null T lymphocytes showed normal development but hyperproliferation upon stimulation, which correlates with hyperinduction of interleukin (IL)-2, IL-4, and interferon (IFN)-gamma. T cell hyperproliferation, but not other autoimmune symptoms, was observed in T cell-specific Mta2 knock-out mice. Mta2 null T cells produced more IL-4 and IFN-gamma under Th2 activation conditions, but normal levels of IL-4 and IFN-gamma under Th1 activation conditions. Furthermore, we found that IL-4 is a direct target gene of Mta2. Our study suggests that Mta2/NuRD is involved in modulating IL-4 and IFN-gamma expression in T cell immune responses, and gene expression in non-T cells plays an important role in controlling autoimmunity.
Highlights
Eling and histone modifying enzymes [1,2,3]
Even though it is well established that histone modification and chromatin remodeling play important roles in lymphocyte differentiation and activation, little is known about the identity of the corresponding enzymes
To gain insight into its function, we generated a mouse model in which a component of the NuRD complex is deleted by gene targeting
Summary
Generation of Mice Carrying Mta22lox and Mta21lox Alleles and Manipulation of Mice—The Mta targeting vector included PGK-Neo and MC1-tk expression cassettes for positive and negative selection, respectively. About 2 ϫ 106 anti-CD3/anti-CD28 mAb-stimulated LN cells were plated in a 24-well plate and cultured for 4 days before harvesting of the supernatant. 2 ϫ 106 CD4ϩ cells were stimulated with anti-CD3 and anti-CD28 mAb, as described, in the presence of recombinant human IL-2 (100units/ml) (nonpolarized condition). For Th2 differentiation, cells were stimulated in the presence of mouse IL-4 (50 ng/ml), anti-IL-12 1 ϫ 105 cells from each polarization condition were harvested and analyzed for IL-4 expression by real-time PCR.
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