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Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors.

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Τίτλος: Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors.
Συγγραφείς: Tak YE; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA, USA.; Department of Pathology, Harvard Medical School, Boston, MA, USA., Boulay G; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Department of Pathology, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Lee L; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA., Iyer S; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA., Perry NT; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA, USA., Schultz HT; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA, USA., Garcia SP; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA., Broye L; Institute of Pathology, Department of Experimental Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland., Horng JE; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA, USA., Rengarajan S; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA., Naigles B; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA., Volorio A; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Institute of Pathology, Department of Experimental Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland., Sander JD; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA, USA.; Department of Pathology, Harvard Medical School, Boston, MA, USA., Gong J; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA, USA., Riggi N; Institute of Pathology, Department of Experimental Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland., Joung JK; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, MA, USA.; Department of Pathology, Harvard Medical School, Boston, MA, USA., Rivera MN; Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.; Department of Pathology, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Πηγή: Cell genomics [Cell Genom] 2022 Apr 13; Vol. 2 (4).
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier, Inc Country of Publication: United States NLM ID: 9918284260106676 Publication Model: Print Cited Medium: Internet ISSN: 2666-979X (Electronic) Linking ISSN: 2666979X NLM ISO Abbreviation: Cell Genom Subsets: PubMed not MEDLINE
Imprint Name(s): Original Publication: [New York] : Elsevier, Inc., [2021]-
Περίληψη: Repeat elements can be dysregulated at a genome-wide scale in human diseases. For example, in Ewing sarcoma, hundreds of inert GGAA repeats can be converted into active enhancers when bound by EWS-FLI1. Here we show that fusions between EWS and GGAA-repeat-targeted engineered zinc finger arrays (ZFAs) can function at least as efficiently as EWS-FLI1 for converting hundreds of GGAA repeats into active enhancers in a Ewing sarcoma precursor cell model. Furthermore, a fusion of a KRAB domain to a ZFA can silence GGAA microsatellite enhancers genome wide in Ewing sarcoma cells, thereby reducing expression of EWS-FLI1-activated genes. Remarkably, this KRAB-ZFA fusion showed selective toxicity against Ewing sarcoma cells compared with non-Ewing cancer cells, consistent with its Ewing sarcoma-specific impact on the transcriptome. These findings demonstrate the value of ZFAs for functional annotation of repeats and illustrate how aberrant microsatellite activities might be regulated for potential therapeutic applications.
Competing Interests: DECLARATION OF INTERESTS J.K.J. has, or had during the course of this research, financial interests in several companies developing gene-editing or epigenetic-editing technology: Beam Therapeutics, Blink Therapeutics, Chroma Medicine, Editas Medicine, EpiLogic Therapeutics, ETx Inc., Excelsior Genomics, Hera Biolabs, Monitor Biotechnologies, Pairwise Plants, Poseida Therapeutics, SeQure Dx Inc., and Verve Therapeutics. J.K.J.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.K.J. is a consultant for Beam Therapeutics, Chroma Medicine, ETx Inc., Pairwise Plants, SeQure Dx Inc., and Verve Therapeutics and is a scientific co-founder of these companies and of Blink Therapeutics, Editas Medicine, EpiLogic Therapeutics, Excelsior Genomics, and Monitor Biotechnologies. G.B., J.K.J., M.N.R., and Y.E.T. are inventors on a patent application that encompasses work described in this paper. J.K.J. and Y.E.T. are inventors on patents or patent applications describing various gene- and epigenetic-editing technologies. M.N.R. receives research support from ACD and Merck Serono for work unrelated to this study. S.I. and S.P.G. are employees of Verve Therapeutics. J.K.J. is a member of the Advisory Board of Cell Genomics.
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Grant Information: DP1 GM105378 United States GM NIGMS NIH HHS; U54 CA231637 United States CA NCI NIH HHS; R01 CA259058 United States CA NCI NIH HHS; R35 GM118158 United States GM NIGMS NIH HHS; R01 CA211707 United States CA NCI NIH HHS; DP1 OD006862 United States OD NIH HHS; R01 CA204954 United States CA NCI NIH HHS
Entry Date(s): Date Created: 20220815 Latest Revision: 20260924
Update Code: 20260924
PubMed Central ID: PMC9374162
DOI: 10.1016/j.xgen.2022.100119
PMID: 35967079
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2666-979X
DOI:10.1016/j.xgen.2022.100119