title: Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome.
abstract: Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642-two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS-U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS-Unewborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.
authors.affiliation: Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.|Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Hyeong-Min
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Sciaky
authors.affiliation: Department of Neurobiology, School of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Hulbert
authors.affiliation: Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pathology, School of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Everitt
authors.affiliation: Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.|Program in Neuroscience, Division of Chemical Biology and Medicinal Chemistry, and NIMH Psychoactive Drug Screening Program, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, USA.|Department of Neurobiology, School of Medicine, Duke University, Durham, North Carolina, USA.|Program in Genetics and Genomics, School of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D018392:Genomic Imprinting; D042421:Histone Code / Q000187:drug effects* / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D020537:RNA, Small Nucleolar / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055517:snRNP Core Proteins / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D020537:RNA, Small Nucleolar; C000601579:SNORD116 RNA, human; C000609194:SNORD116 RNA, mouse; C561310:UNC 0638; C000621860:UNC0642; D055517:snRNP Core Proteins; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases