ABSTRACT
The chromodomain helicase DNA-binding proteins (CHDs) are known to affect transcription through their ability to remodel chromatin and modulate histone deacetylation. In an effort to understand the functional role of the CHD2 in mammals, we have generated a Chd2 mutant mouse model. Remarkably, the Chd2 protein appears to play a critical role in the development, hematopoiesis and tumor suppression. The Chd2 heterozygous mutant mice exhibit increased extramedullary hematopoiesis and susceptibility to lymphomas. At the cellular level, Chd2 mutants are defective in hematopoietic stem cell differentiation, accumulate higher levels of the chromatin-associated DNA damage response mediator, gamma H2AX, and exhibit an aberrant DNA damage response after X-ray irradiation. Our data suggest a direct role for the chromatin remodeling protein in DNA damage signaling and genome stability maintenance.
Subject(s)
DNA Damage , DNA-Binding Proteins/physiology , Liver/pathology , Lymphoma/pathology , Signal Transduction , Animals , Cell Differentiation , Cells, Cultured , Chromatin/genetics , Chromatin/metabolism , Fetus , Hematopoietic Stem Cells/metabolism , Heterozygote , Histones/genetics , Histones/metabolism , Liver/metabolism , Lymphoma/genetics , Lymphoma/metabolism , Mice , Mice, Knockout , X-RaysABSTRACT
Transcriptional repression plays crucial roles in diverse aspects of metazoan development, implying critical regulatory roles for corepressors such as N-CoR and SMRT. Altered patterns of transcription in tissues and cells derived from N-CoR gene-deleted mice and the resulting block at specific points in CNS, erythrocyte, and thymocyte development indicated that N-CoR was a required component of short-term active repression by nuclear receptors and MAD and of a subset of long-term repression events mediated by REST/NRSF. Unexpectedly, N-CoR and a specific deacetylase were also required for transcriptional activation of one class of retinoic acid response element. Together, these findings suggest that specific combinations of corepressors and histone deacetylases mediate the gene-specific actions of DNA-bound repressors in development of multiple organ systems.
Subject(s)
Gene Expression Regulation, Developmental , Nuclear Proteins/genetics , Repressor Proteins/genetics , Transcription, Genetic/physiology , Animals , Diencephalon/embryology , Erythropoiesis/physiology , Female , Fibroblasts/cytology , Fibroblasts/physiology , Gene Deletion , Hematocrit , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Receptor Co-Repressor 1 , T-Lymphocytes/cytology , Thymus Gland/cytology , Thymus Gland/embryology , Yolk Sac/blood supply , Yolk Sac/physiologyABSTRACT
Developing T cells which recognize self-proteins are specifically deleted by the process of negative selection in the thymus. This review summarizes data from both in-vitro and in-vivo systems on the cellular and biochemical requirements that play roles in this process. We first consider the involvement of co-receptors and antigen presenting cells in negative selection. Next, we discuss the involvement of various signalling pathways in thymocyte deletion, particularly under conditions of limiting stimulation. Finally, these data are discussed in terms of how positive and negative selection are regulated during T-cell development.
