表观遗传学医学的新纪元？
A new horizon for epigenetic medicine?
机构信息
Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston MA, 02115, USA.
出版信息
Cell Res. 2013 Mar;23(3):326-8. doi: 10.1038/cr.2012.136. Epub 2012 Sep 18.
Abstract
Histone lysine demethylases are chromatin modifiers that play important roles in many pathological processes such as inflammation and cancer, making them potentially attractive drug targets. In a recent study, Kruidenier et al. provided proof of concept by identifying chemical matters that inhibit demethylation mediated by the two related histone H3 lysine 27 demethylases, KDM6A and 6B (UTX and JMJD3). The KDM6 inhibitor shows remarkable substrate selectivity and can inhibit transcription of a plethora of pro-inflammatory genes in cell culture by altering H3K27me3 level at some of the KDM6 target genes.
摘要
组蛋白赖氨酸去甲基酶是染色质修饰物，在炎症和癌症等许多病理过程中发挥重要作用，使它们成为潜在有吸引力的药物靶点。在最近的一项研究中，Kruidenier 等人通过鉴定抑制由两个相关的组蛋白 H3 赖氨酸 27 去甲基酶 KDM6A 和 6B（UTX 和 JMJD3）介导的去甲基化的化学物质，提供了概念验证。该 KDM6 抑制剂显示出显著的底物选择性，并可以通过改变一些 KDM6 靶基因的 H3K27me3 水平，在细胞培养物中抑制大量促炎基因的转录。
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本文引用的文献
1
A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
Nature. 2012 Aug 16;488(7411):404-8. doi: 10.1038/nature11262.
2
The mutational landscape of lethal castration-resistant prostate cancer.
Nature. 2012 Jul 12;487(7406):239-43. doi: 10.1038/nature11125.
3
The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation.
Genes Dev. 2012 Jun 15;26(12):1364-75. doi: 10.1101/gad.186056.111.
4
Histone methylation: a dynamic mark in health, disease and inheritance.
Nat Rev Genet. 2012 Apr 3;13(5):343-57. doi: 10.1038/nrg3173.
5
Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification.
Cell. 2011 Sep 16;146(6):1016-28. doi: 10.1016/j.cell.2011.08.008.
6
Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.
Nat Genet. 2011 Aug 7;43(9):875-8. doi: 10.1038/ng.907.
7
Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation.
Blood. 2011 Feb 24;117(8):2451-9. doi: 10.1182/blood-2010-11-321208. Epub 2010 Dec 29.
8
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.
Nat Genet. 2010 Feb;42(2):181-5. doi: 10.1038/ng.518. Epub 2010 Jan 17.
9
Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
Nature. 2010 Jan 21;463(7279):360-3. doi: 10.1038/nature08672. Epub 2010 Jan 6.
10
Jmjd3 contributes to the control of gene expression in LPS-activated macrophages.
EMBO J. 2009 Nov 4;28(21):3341-52. doi: 10.1038/emboj.2009.271. Epub 2009 Sep 24.
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