Reik Andreas, Gregory Philip D, Urnov Fyodor D
Sangamo Biosciences, Pt Richmond Tech Center, 501 Canal Blvd, Suite A100, Richmond, California 94804, USA.
Curr Opin Genet Dev. 2002 Apr;12(2):233-42. doi: 10.1016/s0959-437x(02)00291-5.
As alterations in gene expression underlie a considerable proportion of human diseases, correcting such aberrant transcription in vivo is expected to provide therapeutic benefit to the patient. Attempts to control endogenous mammalian genes, however, face a significant obstacle in the form of chromatin. Aberrant gene repression can be alleviated by using small-molecule inhibitors that exert nucleus-wide effects on chromatin-based repressors. Genome-wide chromatin remodeling also occurs during cloning via nuclear transfer, and causes the deregulation of epigenetically controlled genes. Regulation of genes in vivo can be accomplished via the use of designed transcription factors - these result from a fusion of a designed DNA-binding domain based on the zinc finger protein motif to a functional domain of choice.
由于基因表达的改变是相当一部分人类疾病的基础，因此在体内纠正这种异常转录有望为患者带来治疗益处。然而，试图控制内源性哺乳动物基因面临着染色质形式的重大障碍。使用对基于染色质的阻遏物具有全核效应的小分子抑制剂可以减轻异常基因抑制。全基因组染色质重塑也会在通过核移植进行克隆的过程中发生，并导致表观遗传控制基因的失调。体内基因调控可以通过使用设计的转录因子来实现——这些转录因子是基于锌指蛋白基序的设计DNA结合结构域与所选功能结构域融合的结果。
