The mSin3A chromatin-modifying complex is essential for embryogenesis and T-cell development.
The corepressor mSin3A is the core component of a chromatin-modifying complex that is recruited by multiple gene-specific transcriptional repressors. In order to understand the role of mSin3A during development, we generated constitutive germ line as well as conditional msin3A deletions. msin3A deletion in the developing mouse embryo results in lethality at the postimplantation stage, demonstrating that it is an essential gene. Blastocysts derived from preimplantation msin3A null embryos and mouse embryo fibroblasts (MEFs) lacking msin3A display a significant reduction in cell division. msin3A null MEFs also show mislocalization of the heterochromatin protein, HP1alpha, without alterations in global histone acetylation. Heterozygous msin3A(+/-) mice with a systemic twofold decrease in mSin3A protein develop splenomegaly as well as kidney disease indicative of a disruption of lymphocyte homeostasis. Conditional deletion of msin3A from developing T cells results in reduced thymic cellularity and a fivefold decrease in the number of cytotoxic (CD8) T cells, while helper (CD4) T cells are unaffected. We show that CD8 development is dependent on mSin3A at a step downstream of T-cell receptor signaling and that loss of mSin3A specifically decreases survival of double-positive and CD8 T cells. Thus, msin3A is a pleiotropic gene which, in addition to its role in cell cycle progression, is required for the development and homeostasis of cells in the lymphoid lineage.
Cowley
Shaun M
SM
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle WA 98109-1024, USA.
Iritani
Brian M
BM
Mendrysa
Susan M
SM
Xu
Tina
T
Cheng
Pei Feng
PF
Yada
Jason
J
Liggitt
H Denny
HD
Eisenman
Robert N
RN
D000818:Animals; D017209:Apoptosis; D001755:Blastocyst; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D005091:Exons; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D015433:Glomerulonephritis, Membranous; D006570:Heterochromatin / Q000378:metabolism; D006579:Heterozygote; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013163:Splenomegaly; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D000090266:Chromobox Protein Homolog 5; D056264:Sin3 Histone Deacetylase and Corepressor Complex