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Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT-induced pathology while reducing Polycomb Repressive Complex2 core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.<\/jats:p>","DOI":"10.1093\/hmg\/ddx432","type":"journal-article","created":{"date-parts":[[2017,12,20]],"date-time":"2017-12-20T07:43:04Z","timestamp":1513755784000},"page":"649-666","source":"Crossref","is-referenced-by-count":23,"title":["Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington\u2019s disease"],"prefix":"10.1093","volume":"27","author":[{"given":"Wan","family":"Song","sequence":"first","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N\u00f3ra","family":"Zsindely","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Szeged, 6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anik\u00f3","family":"Farag\u00f3","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Szeged, 6726 Szeged, Hungary"},{"name":"Doctoral School in Biology, Faculty of Science and Informatics, University of Szeged, 6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J Lawrence","family":"Marsh","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e1szl\u00f3","family":"Bodai","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA"},{"name":"Department of Biochemistry and Molecular Biology, University of Szeged, 6726 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,12,21]]},"reference":[{"key":"2019071200554626000_ddx432-B1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on huntingtons-disease chromosomes","volume":"72","author":"Macdonald","year":"1993","journal-title":"Cell"},{"key":"2019071200554626000_ddx432-B2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.neuron.2012.05.024","article-title":"Network organization of the huntingtin proteomic interactome in mammalian brain","volume":"75","author":"Shirasaki","year":"2012","journal-title":"Neuron"},{"key":"2019071200554626000_ddx432-B3","doi-asserted-by":"crossref","first-page":"e41423.","DOI":"10.1371\/journal.pone.0041423","article-title":"Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease","volume":"7","author":"McFarland","year":"2012","journal-title":"PLoS One"},{"key":"2019071200554626000_ddx432-B4","doi-asserted-by":"crossref","first-page":"19176","DOI":"10.1073\/pnas.0606373103","article-title":"ESET\/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington\u2019s disease","volume":"103","author":"Ryu","year":"2006","journal-title":"Proc. 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