The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development.
SATB1 is expressed primarily in thymocytes and can act as a transcriptional repressor. SATB1 binds in vivo to the matrix attachment regions (MARs) of DNA, which are implicated in the loop domain organization of chromatin. The role of MAR-binding proteins in specific cell lineages is unknown. We generated SATB1-null mice to determine how SATB1 functions in the T-cell lineage. SATB1-null mice are small in size, have disproportionately small thymi and spleens, and die at 3 weeks of age. At the cellular level, multiple defects in T-cell development were observed. Immature CD3(-)CD4(-)CD8(-) triple negative (TN) thymocytes were greatly reduced in number, and thymocyte development was blocked mainly at the DP stage. The few peripheral CD4(+) single positive (SP) cells underwent apoptosis and failed to proliferate in response to activating stimuli. At the molecular level, among 589 genes examined, at least 2% of genes including a proto-oncogene, cytokine receptor genes, and apoptosis-related genes were derepressed at inappropriate stages of T-cell development in SATB1-null mice. For example, IL-2Ralpha and IL-7Ralpha genes were ectopically transcribed in CD4(+)CD8(+) double positive (DP) thymocytes. SATB1 appears to orchestrate the temporal and spatial expression of genes during T-cell development, thereby ensuring the proper development of this lineage. Our data provide the first evidence that MAR-binding proteins can act as global regulators of cell function in specific cell lineages.
Alvarez
J D
JD
Nippon Roche Research Center, Kamakura 247, Japan.
Yasui
D H
DH
Niida
H
H
Joh
T
T
Loh
D Y
DY
Kohwi-Shigematsu
T
T
D000375:Aging; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D036961:Matrix Attachment Region Binding Proteins; D051379:Mice; D018345:Mice, Knockout; D015530:Nuclear Matrix / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D015375:Receptors, Interleukin-2 / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology* / Q000648:ultrastructure; D013737:Testis / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D036961:Matrix Attachment Region Binding Proteins; D000090063:Proto-Oncogene Mas; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; C076189:SATB1 protein, human