Targeted regulation of imprinted genes by synthetic zinc-finger transcription factors.
Epigenetic control of transcription is essential for mammalian development and its deregulation causes human disease. For example, loss of proper imprinting control at the IGF2-H19 domain is a hallmark of cancer and Beckwith-Wiedemann syndrome, with no targeted therapeutic approaches available. To address this deficiency, we engineered zinc-finger transcription proteins (ZFPs) that specifically activate or repress the IGF2 and H19 genes in a domain-dependent manner. Importantly, we used these ZFPs successfully to reactivate the transcriptionally silent IGF2 and H19 alleles, thus overriding the natural mechanism of imprinting and validating an entirely novel avenue for 'transcription therapy' of human disease.
Jouvenot
Y
Y
Sangamo BioSciences, Inc., Point Richmond Tech Center, Richmond, CA 94804, USA.
Ginjala
V
V
Zhang
L
L
Liu
P-Q
PQ
Oshimura
M
M
Feinberg
A P
AP
Wolffe
A P
AP
Ohlsson
Rolf
R
Gregory
P D
PD
D001506:Beckwith-Wiedemann Syndrome / Q000628:therapy; D005260:Female; D005786:Gene Expression Regulation; D018390:Gene Targeting / Q000379:methods; D016147:Genes, Tumor Suppressor; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007680:Kidney Neoplasms / Q000628:therapy; D008297:Male; D009369:Neoplasms / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D009396:Wilms Tumor / Q000628:therapy; D016335:Zinc Fingers
D014157:Transcription Factors; D007335:Insulin-Like Growth Factor II