A molecular dissection of the repression circuitry of Ikaros.
Ikaros is a key regulator of the hemo-lymphoid system in which it is presumed to function by both potentiating and repressing gene expression. Repression is mediated through two independent domains at the N and C terminus of the protein, both of which can independently recruit the corepressors Mi-2beta, Sin3A, and Sin3B and the Class I histone deacetylases 1 and 2; the N-terminal domain can also associate with the corepressor CtBP. Here we describe a detailed dissection of these two domains and identify the minimal repression modules and the corepressor requirements for their activity. Based on these studies, we describe mutations in a full-length Ikaros protein that abrogate interactions with each of the identified corepressors and abolish the protein's function as a repressor. Finally, we show that, barring CtBP, the Ikaros family members Aiolos, Helios, and Eos can associate with all of the identified corepressors of Ikaros including its newly identified interactors, Class II HDACs.
Koipally
Joseph
J
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Georgopoulos
Katia
K
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D006801:Humans; D051740:Ikaros Transcription Factor; D051379:Mice; D016296:Mutagenesis; D020033:Protein Isoforms / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C492042:SIN3B protein, human; C115812:Sin3b protein, mouse; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D056264:Sin3 Histone Deacetylase and Corepressor Complex