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, Yi Zhang

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)13825-13833
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number20
DOIs
StatePublished - May 16 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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