2014
DOI: 10.1093/nar/gku708
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Analysis of an artificial zinc finger epigenetic modulator: widespread binding but limited regulation

Abstract: Artificial transcription factors (ATFs) and genomic nucleases based on a DNA binding platform consisting of multiple zinc finger domains are currently being developed for clinical applications. However, no genome-wide investigations into their binding specificity have been performed. We have created six-finger ATFs to target two different 18 nt regions of the human SOX2 promoter; each ATF is constructed such that it contains or lacks a super KRAB domain (SKD) that interacts with a complex containing repressive… Show more

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Cited by 61 publications
(67 citation statements)
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“…The functional effects we observed, however, may also be partly caused by the aspecific binding of the EPB41L3-targeting ATFs, as also observed for other ZFPs. 45 Such aspecific binding may result in modulation of off-target genes, although certain ZFATFs might regulate gene expression with single gene resolution. 25,46 A possible explanation for such observed gene specificity may be that most of the off-target promoters have an open chromatin structure which is easily accessible by the ATFs; however, the relative impact of ATFs on actively transcribed genes is small.…”
Section: Discussionmentioning
confidence: 99%
“…The functional effects we observed, however, may also be partly caused by the aspecific binding of the EPB41L3-targeting ATFs, as also observed for other ZFPs. 45 Such aspecific binding may result in modulation of off-target genes, although certain ZFATFs might regulate gene expression with single gene resolution. 25,46 A possible explanation for such observed gene specificity may be that most of the off-target promoters have an open chromatin structure which is easily accessible by the ATFs; however, the relative impact of ATFs on actively transcribed genes is small.…”
Section: Discussionmentioning
confidence: 99%
“…It is possible that multiple sets of zinc fingers in ZFX may recognize a repeating unit of a short motif. Alternatively, it is possible that ZFX utilizes only a subset of its fingers to bind DNA; we have previously described this situation for two artificial six-finger ZNFs (Grimmer et al 2014). To further analyze the ZFX binding preferences, we focused on the AGGCCTAG motif, which is found in >90% of the ZFX peaks in each cell line.…”
Section: Zfx Binds To Cpg Island Promoter Regionsmentioning
confidence: 99%
“…For example, it remains unclear how fusions to different DBDs might influence off-target binding. Previous studies suggest that the addition of a KRAB domain to a ZF can greatly increase the ZF’s off-target interactions [70]. This is in contrast to other studies that did not find evidence that addition of the KRAB domain to dCas9 increased off-target binding [78, 79].…”
Section: Locus-specificitymentioning
confidence: 75%
“…For example, CMEs may have domains that interact with DNA or other proteins located at off-target loci [70]. This sequestering effect can be mitigated by fusing only the core catalytic domains of CMEs to DBDs, or by mutating residues in CMEs to reduce its intrinsic interactions with other binding partners.…”
Section: Locus-specificitymentioning
confidence: 99%