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Specificity assessment of allele selective Zinc Finger Protein Repressors in HD fibroblasts

ABSTRACT: Specificity assessment of allele selective Zinc Finger Protein Repressors in HD fibroblasts

PROVIDER: PRJNA525454 | ENA |

REPOSITORIES: ENA

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Specificity assessment of allele selective Zinc Finger Protein Repressors in HD fibroblasts

Project description:Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range, while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and at least 9 months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological, and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.

2019-06-30 | GSE127820 | GEO

Specificity assessment of allele selective Zinc Finger Protein Repressors in hESC-derived HD neurons

2019-06-30 | GSE127821 | GEO

Specificity assessment of allele selective Zinc Finger Protein Repressors in hESC-derived HD neurons

Project description:Specificity assessment of allele selective Zinc Finger Protein Repressors in hESC-derived HD neurons

| PRJNA525455 | ENA

Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation

Project description:Epigenetic changes at the HTLV-I LTR when targeted with ZFP repressors

2022-12-08 | GSE218440 | GEO

Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation

Project description:Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation

| PRJNA903848 | ENA

Comprehensive screens and a universal zinc finger model enable transcription factor reprogramming 2 factor reprogrammingComprehensive screens and a universal zinc finger model enable transcription factor reprogramming

Project description:Programmable regulation of gene expression promises to be a powerful therapeutic venue for diseases caused by the misexpression of genes, haploinsufficiencies, or gain of function mutations. While dCas9-effector domain fusions have been used to alter expression levels, their in vivo application is limited by size and immunogenicity. Conversely, the Cys2His2 Zinc Finger domain offers ideal characteristics for in vivo use. However, their intricate engagement with the DNA has made the design of Zinc Finger arrays challenging. We here describe the screening of 49 billion protein-DNA interactions and development of the first deep learning model that solves Zinc Finger design for any genomic target. We demonstrate the versatility of designed Zinc Fingers as nucleases and as activators or repressors by seamlessly reprogramming human transcription factors.

2022-11-01 | GSE215330 | GEO

Astrocyte molecular signatures during Huntington’s disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors

Project description:Astrocyte molecular signatures during Huntington’s disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors

| PRJNA513983 | ENA

Genomic targets of the KRAB and scan domain-containing zinc finger protein 263 (ZNF263).

Project description:Half of all human transcription factors use C2H2 zinc finger domains to specify site-specific DNA binding and yet very little is known about their role in gene regulation. Based on in vitro studies, a zinc finger code has been developed that predicts a binding motif for a particular zinc finger factor (ZNF). However, very few studies have performed genome-wide analyses of ZNF binding patterns and thus it is not clear if the binding code developed in vitro will be useful for identifying target genes of a particular ZNF. We performed genome-wide ChIP-seq for ZNF263, a C2H2 ZNF that contains 9 finger domains, a KRAB repression domain, and a SCAN domain and identified more than 5000 binding sites in K562 cells. Our results suggest that ZNF263 binds to a 24 nt site which differs from the motif predicted by the zinc finger code in several positions. Interestingly, many of the ZNF263 binding sites are located within the transcribed region of the target gene. Although ZNFs containing a KRAB domain are thought to function mainly as transcriptional repressors, many of the ZNF263 target genes are expressed at high levels. To address the biological role of ZNF263, we identified genes whose expression was altered by treatment of cells with ZNF263-specific siRNAs. Our results suggest that ZNF263 can have both positive and negative effects on transcriptional regulation of its target genes. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Examination of ZNF263 ChIP-seq in K562 cells.

2009-12-03 | E-GEOD-19235 | biostudies-arrayexpress

Sequence specificity is obtained from the majority of modular C2H2 zinc-finger arrays

Project description:C2H2 zinc fingers (C2H2-ZFs) are the most prevalent type of vertebrate DNA-binding domain, and typically appear in tandem arrays (ZFAs), with sequential C2H2-ZFs each contacting 3 (or more) sequential bases. C2H2-ZFs can be assembled in a modular fashion, providing one explanation for their remarkable evolutionary success. Given a set of modules with defined 3-base specificities, modular assembly also presents a way to construct artificial proteins with specific DNA-binding preferences. However, a recent survey of a large number of three-finger ZFAs engineered by modular assembly reported high failure rates (~70%), casting doubt on the generality of modular assembly. Here, we used protein-binding microarrays to analyze 28 ZFAs that failed in the aforementioned study. Most (17) preferred specific sequences, which in all but one case resembled the intended target sequence. Like natural ZFAs, the engineered ZFAs typically yielded degenerate motifs, binding dozens to hundreds of related individual sequences. Thus, the failure of these proteins in previous assays is not due to lack of sequence-specific DNA-binding activity. Our findings underscore the relevance of individual C2H2-ZF sequence specificities within tandem arrays, and support the general ability of modular assembly to produce ZFAs with sequence-specific DNA-binding activity. Protein binding microarray (PBM) experiments were performed for a set of 20 artificial zinc finger arrays (ZFAs). Briefly, the PBMs involved binding GST-tagged DNA-binding proteins to two double-stranded 44K Agilent microarrays, each containing a different DeBruijn sequence design, in order to determine their sequence preferences. The method is described in Berger et al., Nature Biotechnology 2006.

2010-12-02 | E-GEOD-25723 | biostudies-arrayexpress

Downregulation of KRAB zinc finger proteins in 5-fluorouracil resistant colorectal cancer cells

Project description:The radio-chemotherapy with 5-fluorouracil (5-FU) is the standard of care treatment for patients with locally advanced rectal cancer (LARC) but it is only effective for a third of them. The proteomic and transcriptomic response of three colorectal cancer (CRC) cell lines to 5-FU and radiation was assessed and correlated with their genetic background. The induction of a 5-FU-resistance in those cell lines negatively affects the levels of transcripts corresponding to Krüppel-associated box (KRAB)-containing zinc finger proteins (ZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter are down-regulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights possible new mechanisms involved in resistance to treatment and therefore potential new therapeutic targets to overcome this resistance.

2022-05-19 | PXD020000 | Pride

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