Zinc Finger Protein 521 regulates early hematopoiesis through cell extrinsic mechanisms in the bone marrow microenvironment
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ABSTRACT:
PROVIDER: PRJNA451481 | ENA |
REPOSITORIES: ENA
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Project description:Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development through soluble microenvironmental proteins. Mice with inactivated Zfp521 genes (Zfp521-/-) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes BM microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis and towards granulopoiesis. These results advance our understanding of ZFP521’s role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.
2018-07-10 | GSE113543 | GEO
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Project description:C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2 arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. We have determined the binding sites and motifs of 119 C2H2 zinc finger proteins and the expression pattern of 80 cell lines overexpressing C2H2 zinc finger proteins in order to study the role of C2H2 zinc finger proteins in gene regulation. We expressed GFP-tagged C2H2-ZF proteins in stable transgenic HEK293 cells. Total RNA was isolated using Trizol and sequencing libraries were constructed using TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Gold or TruSeq RNA Library Preparation Kit v2.
2016-10-25 | E-GEOD-76495 | biostudies-arrayexpress
Project description:C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2 arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. We have determined the binding sites and motifs of 119 C2H2 zinc finger proteins and the expression pattern of 80 cell lines overexpressing C2H2 zinc finger proteins in order to study the role of C2H2 zinc finger proteins in gene regulation.
2016-10-25 | GSE76495 | GEO
Project description:We have identified protein protein interactions of 118 C2H2 zinc finger proteins by AP-MS using GFP-tagged constructs in order to understand their role in transcription regulation.
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Project description:Zinc Finger Nucleases (ZFNs) facilitate precise editing of DNA enabling targeted genomic modifications in vivo. ZFNs have been employed to obtain genetically modified plants and animals, and cell-based therapies utilizing ZFNs are undergoing clinical trials. However, many ZFNs display dose-dependent toxicity presumably due to the generation of undesired double stranded breaks at off-target sites within the genome. To evaluate the parameters influencing the functional specificity of ZFNs, we compared the in vivo activity of ZFN variants targeting the zebrafish kdrl locus, which display both high on-target activity and dose-dependent toxicity. We evaluated their functional specificity by assessing lesion frequency at 141 potential off-target sites within the zebrafish genome using Illumina sequencing. Only a minority of these off-target sites displayed significant lesion frequency with kdrl ZFNs. Furthermore, we find that active off-target sites appear to be defined by the thermodynamics of zinc finger-DNA recognition. Surprisingly, we observed that the zinc finger protein specificity and the choice of the engineered dimerization domain of the FokI nuclease could independently influence the fidelity of these ZFNs. The results of this study have implications for the assessment of likely off-target sites within a genome and point to both ZFP-dependent and –independent mechanisms of potential improvement for engineering ZFNs with higher levels of precision. Examined lesions at 141 off-target sites for various treatments of ZFNs and compare to the untreated sample stage 1: raw read but missing quality values stage 2: fastq files available from SRA
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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.
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Project description:Cys2-His2 Zinc finger genes (ZNFs) form the largest family of transcription factors in metazoans. Zebrafish posess a subfamily characterized by the presence of a domain dubbed Fish N-terminal Zinc finger associated (FiNZ). FiNZ-ZNFs are expressed at the onset of zygotic genome activation in zebrafishh, and blocking FiNZ-ZNF translation using morpholinos during early zebrafish embryogenesis results in a broad de-repression of young, transcriptionally active TEs.
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Project description:To define the sequence preference of SALL4 C2H2 zinc finger domains, we performed SELEX coupled with high-throughput sequencing (HT-SELEX) using the purified SALL4 ZFC1, ZFC2 and ZFC4 domains combined with no protein control experiment.
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Project description:Zinc Finger Nucleases (ZFNs) facilitate precise editing of DNA enabling targeted genomic modifications in vivo. ZFNs have been employed to obtain genetically modified plants and animals, and cell-based therapies utilizing ZFNs are undergoing clinical trials. However, many ZFNs display dose-dependent toxicity presumably due to the generation of undesired double stranded breaks at off-target sites within the genome. To evaluate the parameters influencing the functional specificity of ZFNs, we compared the in vivo activity of ZFN variants targeting the zebrafish kdrl locus, which display both high on-target activity and dose-dependent toxicity. We evaluated their functional specificity by assessing lesion frequency at 141 potential off-target sites within the zebrafish genome using Illumina sequencing. Only a minority of these off-target sites displayed significant lesion frequency with kdrl ZFNs. Furthermore, we find that active off-target sites appear to be defined by the thermodynamics of zinc finger-DNA recognition. Surprisingly, we observed that the zinc finger protein specificity and the choice of the engineered dimerization domain of the FokI nuclease could independently influence the fidelity of these ZFNs. The results of this study have implications for the assessment of likely off-target sites within a genome and point to both ZFP-dependent and –independent mechanisms of potential improvement for engineering ZFNs with higher levels of precision.
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