Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling.
Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling.
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DOI：
10.1038/s41467-018-03476-6
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发表时间：
2018-03-13
影响因子：
16.6
通讯作者：
Huse JT
中科院分区：
文献类型：
--
作者：
Danussi C;Bose P;Parthasarathy PT;Silberman PC;Van Arnam JS;Vitucci M;Tang OY;Heguy A;Wang Y;Chan TA;Riggins GJ;Sulman EP;Lang FF;Creighton CJ;Deneen B;Miller CR;Picketts DJ;Kannan K;Huse JT
SWI/SNF染色质调节因子ATRX的突变失活经常发生在神经胶质瘤中，神经胶质瘤是最常见的原发性脑肿瘤。ATRX缺陷是否以及如何通过表观基因组失调促进肿瘤发生尚不清楚，尽管其最近在基因组不稳定性和端粒功能障碍中的作用。在这里，我们报告说，Atrx的损失概括了典型的疾病表型和分子特征，在假定的胶质瘤细胞的起源，诱导细胞的运动，虽然也转移分化状态和潜力向星形胶质细胞，而不是神经元的组织发生概况。此外，Atrx缺陷驱动染色质可及性、组蛋白组成和转录的广泛变化，其分布几乎完全限于通常由蛋白质结合的基因组位点。最后，在体外介导特定Atrx缺陷表型的Atrx的直接基因靶标在ATRX突变的人胶质瘤中表现出类似的选择性错误表达。这些发现表明，ATRX缺陷及其表观基因组后遗症足以在适当的细胞和分子背景下诱导疾病定义的致癌表型。ATRX失活经常发生在胶质瘤中。在这里，作者探讨了ATRX失活在肿瘤发生中的作用，强调了ATRX缺陷驱动的表观基因组变化，影响了对致癌表型至关重要的基因的表达。
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts. ATRX inactivation frequently occurs in glioma. Here, the authors explore the role of ATRX inactivation in oncogenesis, highlighting ATRX deficiency driven epigenomic changes that influence the expression of genes crucial to the oncogenic phenotype.
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影响因子：
10.5
作者：
Drane, Pascal;Ouararhni, Khalid;Hamiche, Ali
通讯作者：
Hamiche, Ali
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
Daxx/Atrx 复合物通过促进 H3K9 三甲基化在 DNA 低甲基化过程中保护串联重复元件
影响因子：
23.9
作者：
He Q;Kim H;Huang R;Lu W;Tang M;Shi F;Yang D;Zhang X;Huang J;Liu D;Songyang Z
通讯作者：
Songyang Z
影响因子：
3.7
作者：
Clynes D;Jelinska C;Xella B;Ayyub H;Taylor S;Mitson M;Bachrati CZ;Higgs DR;Gibbons RJ
通讯作者：
Gibbons RJ
影响因子：
--
作者：
Borodovsky A;Salmasi V;Turcan S;Fabius AW;Baia GS;Eberhart CG;Weingart JD;Gallia GL;Baylin SB;Chan TA;Riggins GJ
通讯作者：
Riggins GJ