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突变型亨廷顿蛋白通过 Cdx2 诱导 ATRX 表达，调节亨廷顿病的异染色质凝聚和病变。

ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease.

机构信息

VA Boston Healthcare System, MA, USA.

出版信息

Cell Death Differ. 2012 Jul;19(7):1109-16. doi: 10.1038/cdd.2011.196. Epub 2012 Jan 13.

DOI:10.1038/cdd.2011.196
PMID:22240898
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3374076/
Abstract

Aberrant chromatin remodeling is involved in the pathogenesis of Huntington's disease (HD) but the mechanism is not known. Herein, we report that mutant huntingtin (mtHtt) induces the transcription of alpha thalassemia/mental retardation X linked (ATRX), an ATPase/helicase and SWI/SNF-like chromatin remodeling protein via Cdx-2 activation. ATRX expression was elevated in both a cell line model and transgenic model of HD, and Cdx-2 occupancy of the ATRX promoter was increased in HD. Induction of ATRX expanded the size of promyelocytic leukemia nuclear body (PML-NB) and increased trimethylation of H3K9 (H3K9me3) and condensation of pericentromeric heterochromatin, while knockdown of ATRX decreased PML-NB and H3K9me3 levels. Knockdown of ATRX/dXNP improved the hatch rate of fly embryos expressing mtHtt (Q127). ATRX/dXNP overexpression exacerbated eye degeneration of eye-specific mtHtt (Q127) expressing flies. Our findings suggest that transcriptional alteration of ATRX by mtHtt is involved in pericentromeric heterochromatin condensation and contributes to the pathogenesis of HD.

摘要

染色质重塑异常参与亨廷顿病（HD）的发病机制，但具体机制尚不清楚。本研究报告称，突变型亨廷顿蛋白（mtHtt）通过 Cdx-2 激活诱导α地中海贫血/智力低下 X 连锁（ATRX）的转录，ATRX 是一种 ATP 酶/解旋酶和 SWI/SNF 样染色质重塑蛋白。HD 的细胞系模型和转基因模型中 ATRX 的表达均升高，HD 中 ATRX 启动子的 Cdx-2 占有率增加。ATRX 的诱导扩大了早幼粒细胞白血病核体（PML-NB）的大小，并增加了 H3K9 的三甲基化（H3K9me3）和着丝粒周围异染色质的浓缩，而 ATRX 的敲低则降低了 PML-NB 和 H3K9me3 水平。ATRX/dXNP 的敲低可提高表达 mtHtt（Q127）的果蝇胚胎的孵化率。ATRX/dXNP 的过表达加剧了特异性表达 mtHtt（Q127）的果蝇的眼部退化。我们的研究结果表明，mtHtt 对 ATRX 的转录改变参与了着丝粒周围异染色质的浓缩，并导致 HD 的发病机制。

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ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease.突变型亨廷顿蛋白通过 Cdx2 诱导 ATRX 表达，调节亨廷顿病的异染色质凝聚和病变。
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本文引用的文献

1
The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9.ATRX-ADD 结构域与 H3 尾部肽结合，并读取 K4 和 K9 的组合甲基化状态。
Hum Mol Genet. 2011 Jun 1;20(11):2195-203. doi: 10.1093/hmg/ddr107. Epub 2011 Mar 18.
2
Loss of maternal ATRX results in centromere instability and aneuploidy in the mammalian oocyte and pre-implantation embryo.母源 ATRX 的缺失导致哺乳动物卵母细胞和着床前胚胎的着丝粒不稳定和非整倍体。
PLoS Genet. 2010 Sep 23;6(9):e1001137. doi: 10.1371/journal.pgen.1001137.
3
dXNP/DATRX increases apoptosis via the JNK and dFOXO pathway in Drosophila neurons.在果蝇神经元中，dXNP/DATRX通过JNK和dFOXO途径增加细胞凋亡。
Biochem Biophys Res Commun. 2009 Jun 26;384(2):160-6. doi: 10.1016/j.bbrc.2009.04.112. Epub 2009 May 4.
4
Patient mutations alter ATRX targeting to PML nuclear bodies.患者突变改变了ATRX定位于PML核体的过程。
Eur J Hum Genet. 2008 Feb;16(2):192-201. doi: 10.1038/sj.ejhg.5201943. Epub 2007 Oct 24.
5
dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun-N-terminal kinase activation.dXNP是XNP/ATRX的果蝇同源物，通过激活Jun-氨基末端激酶诱导细胞凋亡。
FEBS Lett. 2007 Jun 12;581(14):2625-32. doi: 10.1016/j.febslet.2007.05.005. Epub 2007 May 11.
6
Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation.导致遗传性智力迟钝的突变会破坏染色质蛋白MECP2和ATRX之间的相互作用。
Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2709-14. doi: 10.1073/pnas.0608056104. Epub 2007 Feb 12.
7
ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease.ESET/SETDB1基因表达与组蛋白H3（K9）三甲基化在亨廷顿舞蹈病中的研究
Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19176-81. doi: 10.1073/pnas.0606373103. Epub 2006 Dec 1.
8
Mechanisms of disease: Histone modifications in Huntington's disease.疾病机制：亨廷顿舞蹈症中的组蛋白修饰
Nat Clin Pract Neurol. 2006 Jun;2(6):330-8. doi: 10.1038/ncpneuro0199.
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Regulation of higher-order chromatin structures by nucleosome-remodelling factors.核小体重塑因子对高阶染色质结构的调控
Curr Opin Genet Dev. 2006 Apr;16(2):151-6. doi: 10.1016/j.gde.2006.02.006. Epub 2006 Feb 28.
10
Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons.抗氧化剂可调节神经元中线粒体蛋白激酶A，并增加环磷腺苷效应元件结合蛋白（CREB）与线粒体基因组D环DNA的结合。
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13915-20. doi: 10.1073/pnas.0502878102. Epub 2005 Sep 16.