Abstract
The transcriptional repressor BCL-6 regulates B lymphocyte cell fate during the germinal center reaction by preventing terminal differentiation of B lymphocytes into plasma cells until appropriate signals are received. Here, we report a cofactor, MTA3, a cell type-specific subunit of the corepressor complex Mi-2/NuRD, for BCL-6-dependent cell fate determination. MTA3 is expressed in the same pattern in germinal centers as BCL-6. BCL-6 physically interacts with Mi-2/NuRD and this interaction is sensitive to BCL-6 acetylation status. Depletion of MTA3 by RNAi impairs BCL-6-dependent repression and alters the cell-specific transcriptional pattern characteristic of the B lymphocyte. Remarkably, exogenous expression of BCL-6 in a plasma cell line leads, in an MTA3-dependent manner, to repression of plasma cell-specific transcripts, reactivation of the B cell transcriptional program, expression of B lymphocyte cell surface markers, and reprogramming of cell fate.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Acetylation
-
Adenosine Triphosphatases / genetics
-
Adenosine Triphosphatases / metabolism*
-
Antigens, Surface / genetics
-
Antigens, Surface / metabolism
-
Autoantigens / genetics
-
Autoantigens / metabolism*
-
B-Lymphocytes / immunology
-
B-Lymphocytes / metabolism*
-
Cell Differentiation / genetics*
-
Cell Differentiation / immunology
-
Cell Lineage / genetics*
-
Cell Lineage / immunology
-
DNA Helicases / genetics
-
DNA Helicases / metabolism*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Genes, Regulator / genetics
-
HeLa Cells
-
Histone Deacetylases / genetics
-
Histone Deacetylases / metabolism*
-
Humans
-
Lymphocyte Activation / genetics
-
Mi-2 Nucleosome Remodeling and Deacetylase Complex
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism*
-
Plasma Cells / immunology
-
Plasma Cells / metabolism
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-bcl-6
-
RNA Interference
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Transcriptional Activation / genetics
Substances
-
Antigens, Surface
-
Autoantigens
-
CHD4 protein, human
-
DNA-Binding Proteins
-
MTA3 protein, human
-
Neoplasm Proteins
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-6
-
Repressor Proteins
-
Transcription Factors
-
Histone Deacetylases
-
Mi-2 Nucleosome Remodeling and Deacetylase Complex
-
Adenosine Triphosphatases
-
DNA Helicases