{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T19:21:20Z","timestamp":1784661680688,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T00:00:00Z","timestamp":1590019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007661","name":"Netherlands Institute of Government","doi-asserted-by":"publisher","award":["FES0908"],"award-info":[{"award-number":["FES0908"]}],"id":[{"id":"10.13039\/501100007661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["91786373"],"award-info":[{"award-number":["91786373"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"publisher","award":["H2020-MSCA-ITN-2014-ETN 642691"],"award-info":[{"award-number":["H2020-MSCA-ITN-2014-ETN 642691"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["40-00506-98-9021"],"award-info":[{"award-number":["40-00506-98-9021"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epigenetic editing, an emerging technique used for the modulation of gene expression in mammalian cells, is a promising strategy to correct disease-related gene expression. Although epigenetic reprogramming results in sustained transcriptional modulation in several in vivo models, further studies are needed to develop this approach into a straightforward technology for effective and specific interventions. Important goals of current research efforts are understanding the context-dependency of successful epigenetic editing and finding the most effective epigenetic effector(s) for specific tasks. Here we tested whether the fibrosis- and cancer-associated PLOD2 gene can be repressed by the DNA methyltransferase M.SssI, or by the non-catalytic Kr\u00fcppel associated box (KRAB) repressor directed to the PLOD2 promoter via zinc finger- or CRISPR-dCas9-mediated targeting. M.SssI fusions induced de novo DNA methylation, changed histone modifications in a context-dependent manner, and led to 50%\u201370% reduction in PLOD2 expression in fibrotic fibroblasts and in MDA-MB-231 cancer cells. Targeting KRAB to PLOD2 resulted in the deposition of repressive histone modifications without DNA methylation and in almost complete PLOD2 silencing. Interestingly, both long-term TGF\u03b21-induced, as well as unstimulated PLOD2 expression, was completely repressed by KRAB, while M.SssI only prevented the TGF\u03b21-induced PLOD2 expression. Targeting transiently expressed dCas9-KRAB resulted in sustained PLOD2 repression in HEK293T and MCF-7 cells. Together, these findings point to KRAB outperforming DNA methylation as a small potent targeting epigenetic effector for silencing TGF\u03b21-induced and uninduced PLOD2 expression.<\/jats:p>","DOI":"10.3390\/ijms21103634","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T11:31:18Z","timestamp":1590060678000},"page":"3634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["KRAB-Induced Heterochromatin Effectively Silences PLOD2 Gene Expression in Somatic Cells and Is Resilient to TGF\u03b21 Activation"],"prefix":"10.3390","volume":"21","author":[{"given":"Rutger A. F.","family":"Gjaltema","sequence":"first","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"},{"name":"MATRIX Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9sir\u00e9e","family":"Goubert","sequence":"additional","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Huisman","sequence":"additional","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consuelo del","family":"Pilar Garc\u00eda Tobilla","sequence":"additional","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mih\u00e1ly","family":"Koncz","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Biological Research Centre, H-6726 Szeged, Hungary"},{"name":"Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pytrick G.","family":"Jellema","sequence":"additional","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"},{"name":"MATRIX Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8515-2614","authenticated-orcid":false,"given":"Dandan","family":"Wu","sequence":"additional","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uilke","family":"Brouwer","sequence":"additional","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"},{"name":"MATRIX Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-3085","authenticated-orcid":false,"given":"Antal","family":"Kiss","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Biological Research Centre, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2922-4836","authenticated-orcid":false,"given":"Pernette J.","family":"Verschure","sequence":"additional","affiliation":[{"name":"Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud A.","family":"Bank","sequence":"additional","affiliation":[{"name":"MATRIX Research Group, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7416-2788","authenticated-orcid":false,"given":"Marianne G.","family":"Rots","sequence":"additional","affiliation":[{"name":"Epigenetic Editing Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 EA11, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41576-018-0074-2","article-title":"Clinical epigenetics: Seizing opportunities for translation","volume":"20","author":"Berdasco","year":"2019","journal-title":"Nat. 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