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J. Biol. Chem., Vol. 283, Issue 20, 13825-13833, May 16, 2008

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Inactivation of NuRD Component Mta2 Causes Abnormal T Cell Activation and Lupus-like Autoimmune Disease in Mice^*

Xiangdong Lu, Grigoriy I. Kovalev^¶, Hua Chang^||, Eric Kallin, Geoffrey Knudsen^¶, Li Xia, Nilamadhab Mishra^**, Phillip Ruiz, En Li^||, Lishan Su^¶1, and Yi Zhang, Investigator of the Howard Hughes Medical Institute²

From the Howard Hughes Medical Institute, Departments of Biochemistry and Biophysics and ^¶Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, the ^||Models of Disease Center, Novartis Institutes for Biomedical Research Inc., Cambridge, Massachusetts 02139, the ^**Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, and the Department of Pathology, University of Miami, Miami, Florida 33136

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)-. 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- under Th2 activation conditions, but normal levels of IL-4 and IFN- 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- expression in T cell immune responses, and gene expression in non-T cells plays an important role in controlling autoimmunity.

Received for publication, February 19, 2008 , and in revised form, March 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM63067 (to Y. Z.) and AI48407 and HL72240 (to L. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: 100 West Dr., UNC-Chapel Hill, CB7295, Chapel Hill, NC 27599-7295. Fax: 919-966-8212; E-mail: lsu{at}med.unc.edu. ² To whom correspondence may be addressed: 100 West Dr., UNC-Chapel Hill, CB7295, Chapel Hill, NC 27599-7295. Fax: 919-966-4330; E-mail: yi_zhang{at}med.unc.edu.

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