Antagonistic interactions between Ikaros and the chromatin remodeler Mi-2beta determine silencer activity and Cd4 gene expression.
Lineage commitment is induced by changes in gene expression dictated by the intimate interaction between transcription factors and chromatin regulators. Here, we revealed the antagonistic interplay between Ikaros and its associate the chromatin remodeler Mi-2beta during T cell development, as exemplified by the regulation of Cd4 expression. Loss of Ikaros or Mi-2beta led to activation or repression, respectively, of the Cd4 locus at inappropriate stages of development. Their combined mutation reverted to normal CD4 expression. In double-negative thymocytes, Ikaros binding to the Cd4 silencer contributed to its repressive activity. In double-positive thymocytes, concomitant binding of Mi-2beta with Ikaros to the Cd4 silencer caused silencer inactivation, thereby allowing for CD4 expression. Mi-2beta facilitated recruitment of histone acetyl transferases to the silencer. This recruitment possibly antagonized Ikaros and associated repressive activities. Thus, concomitant interactions between functionally opposing chromatin-regulating machineries are an important mode of gene regulation during lineage determination.
Naito
Taku
T
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Gómez-Del Arco
Pablo
P
Williams
Christine J
CJ
Georgopoulos
Katia
K
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage; D004265:DNA Helicases; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D009154:Mutation; D037941:Silencer Elements, Transcriptional; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
D015704:CD4 Antigens; D051740:Ikaros Transcription Factor; D000251:Adenosine Triphosphatases; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases