Novel activation domain derived from Che-1 cofactor coupled with the artificial protein Jazz drives utrophin upregulation.
Our aim is to upregulate the expression level of the dystrophin related gene utrophin in Duchenne muscular dystrophy, thus complementing the lack of dystrophin functions. To this end, we have engineered synthetic zinc finger based transcription factors. We have previously shown that the artificial three-zinc finger protein named Jazz fused with the Vp16 activation domain, is able to bind utrophin promoter A and to increase the endogenous level of utrophin in transgenic mice. Here, we report on an innovative artificial protein, named CJ7, that consists of Jazz DNA binding domain fused to a novel activation domain derived from the regulatory multivalent adaptor protein Che-1/AATF. This transcriptional activation domain is 100 amino acids in size and it is very powerful as compared to the Vp16 activation domain. We show that CJ7 protein efficiently promotes transcription and accumulation of the acetylated form of histone H3 on the genomic utrophin promoter locus.
Desantis
Agata
A
Istituto di Biologia e Patologia Molecolari, CNR, c/o Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
Onori
Annalisa
A
Di Certo
Maria Grazia
MG
Mattei
Elisabetta
E
Fanciulli
Maurizio
M
Passananti
Claudio
C
Corbi
Nicoletta
N
D000107:Acetylation / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015202:Protein Engineering; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D049411:Utrophin / Q000235:genetics* / Q000378:metabolism
C402637:AATF protein, human; D051017:Apoptosis Regulatory Proteins; C540197:CJ7 protein; D004268:DNA-Binding Proteins; D006657:Histones; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; D049411:Utrophin