Inactivation of NuRD component Mta2 causes abnormal T cell activation and lupus-like autoimmune disease in mice.
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.
Lu
Xiangdong
X
Howard Hughes Medical Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Kovalev
Grigoriy I
GI
Chang
Hua
H
Kallin
Eric
E
Knudsen
Geoffrey
G
Xia
Li
L
Mishra
Nilamadhab
N
Ruiz
Phillip
P
Li
En
E
Su
Lishan
L
Zhang
Yi
Y
D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000378:metabolism*; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism*; D008178:Lupus Erythematosus, Cutaneous / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology
D002352:Carrier Proteins; C529798:Mta2 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex