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TET enzymes catalyze hydroxymethylation of methylated DNA, reactivating gene expression. We here report generation of a high-fidelity CRISPR\/Cas9-based gene-specific dioxygenase by fusing an endonuclease deactivated high-fidelity Cas9 (dHFCas9) to TET3 catalytic domain (TET3CD), targeted to specific genes by guiding RNAs (sgRNA). We demonstrate use of this technology in four different anti-fibrotic genes in different cell types in vitro, among them RASAL1 and Klotho, both hypermethylated in kidney fibrosis. Furthermore, in vivo lentiviral delivery of the Rasal1-targeted fusion protein to interstitial cells and of the Klotho-targeted fusion protein to tubular epithelial cells each results in specific gene reactivation and attenuation of fibrosis, providing gene-specific demethylating technology in a disease model.<\/jats:p>","DOI":"10.1038\/s41467-018-05766-5","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T12:16:37Z","timestamp":1535026597000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["High-fidelity CRISPR\/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis"],"prefix":"10.1038","volume":"9","author":[{"given":"Xingbo","family":"Xu","sequence":"first","affiliation":[]},{"given":"Xiaoying","family":"Tan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4357-9863","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Tampe","sequence":"additional","affiliation":[]},{"given":"Tim","family":"Wilhelmi","sequence":"additional","affiliation":[]},{"given":"Melanie S.","family":"Hulshoff","sequence":"additional","affiliation":[]},{"given":"Shoji","family":"Saito","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7145-0533","authenticated-orcid":false,"given":"Tobias","family":"Moser","sequence":"additional","affiliation":[]},{"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[]},{"given":"Gerd","family":"Hasenfuss","sequence":"additional","affiliation":[]},{"given":"Elisabeth M.","family":"Zeisberg","sequence":"additional","affiliation":[]},{"given":"Michael","family":"Zeisberg","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2018,8,29]]},"reference":[{"key":"5766_CR1","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1038\/nrneph.2014.14","volume":"10","author":"D Tampe","year":"2014","unstructured":"Tampe, D., & Zeisberg, M. 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The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3509"}}