Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome.
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome.
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DOI：
10.1038/nm.4257
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发表时间：
2017-03
期刊：
影响因子：
82.9
通讯作者：
Jiang YH
中科院分区：
文献类型：
--
作者：
Kim Y;Lee HM;Xiong Y;Sciaky N;Hulbert SW;Cao X;Everitt JI;Jin J;Roth BL;Jiang YH
Prader-Willi综合征（PWS）是一种由15q11-q13染色体区域父本表达基因缺失引起的印记疾病。该区域的印迹基因表达调控由印迹中心（PWS-IC）协调。在患有PWS的个体中，母体染色体上负责PWS的基因存在，但在表观遗传上受到抑制，这为使用表观遗传治疗来恢复母体PWS相关基因的表达提供了机会。通过bb0009000个小分子的高含量筛选（HCS），我们发现UNC0638和unc0642两种常染色质组蛋白赖氨酸n -甲基转移酶-2 （EHMT2，也称为G9a）的选择性抑制剂激活了PWS潜在候选基因的母源(m)拷贝，包括SnoRNA簇SNORD116，在PWS人细胞和PWS小鼠模型（小鼠模型以下称为m+/pΔS−U）中，PWS小鼠模型携带小核糖核蛋白N （Snrpn (S)）到泛素蛋白连接酶E3A （Ube3a (U)）的父系缺失(p)。通过亚硫酸盐基因组测序分析，UNC0642和UNC0638都导致PWS-IC组蛋白H3赖氨酸9 （H3K9me2）的二甲基化选择性降低，而不改变DNA甲基化。这表明组蛋白修饰对PWS候选基因的印迹至关重要。UNC0642通过改善m+/pΔS−U新生幼鼠的生存和生长，在PWS小鼠模型中显示出治疗作用。这项研究为PWS的表观遗传学治疗提供了第一个原理证明。
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−U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.
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影响因子：
64.8
作者：
Huang, Hsien-Sung;Allen, John A.;Mabb, Angela M.;King, Ian F.;Miriyala, Jayalakshmi;Taylor-Blake, Bonnie;Sciaky, Noah;Dutton, J. Walter, Jr.;Lee, Hyeong-Min;Chen, Xin;Jin, Jian;Bridges, Arlene S.;Zylka, Mark J.;Roth, Bryan L.;Philpot, Benjamin D.
通讯作者：
Philpot, Benjamin D.
影响因子：
5.2
作者：
Bieth, Eric;Eddiry, Sanaa;Tauber, Maithe
通讯作者：
Tauber, Maithe
影响因子：
5.2
作者：
Cassidy, Suzanne B.;Driscoll, Daniel J.
通讯作者：
Driscoll, Daniel J.
影响因子：
5.2
作者：
Kanber, Deniz;Giltay, Jacques;Buiting, Karin
通讯作者：
Buiting, Karin
影响因子：
2.7
作者：
Le Meur, E;Watrin, F;Muscatelli, F
通讯作者：
Muscatelli, F