Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment.
Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment.
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DOI：
10.1007/s00018-005-5318-6
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发表时间：
2005-11
影响因子：
8
通讯作者：
Lattanzi, G
中科院分区：
文献类型：
--
作者：
Columbaro, M;Capanni, C;Mattioli, E;Novelli, G;Parnaik, VK;Squarzoni, S;Maraldi, NM;Lattanzi, G
Hutchinson-Gilford progeria（HGPS）是一种与LMNA突变相关的早衰综合征。携带G608 G LMNA突变的早衰细胞的特征在于突变的核纤层蛋白A前体（早老蛋白）的积累、核异形和染色质解体。在培养的HGPS成纤维细胞，我们发现恶化的细胞表型与患者的年龄，主要包括增加核形状异常，早老蛋白积累和异染色质丢失。此外，转录本分布改变HGPS细胞核，由不同的技术确定。为了改善细胞表型，我们应用影响蛋白质法尼基化或染色质排列的药物进行治疗。我们的研究结果表明，与mevinolin和组蛋白脱乙酰酶抑制剂restatin A的联合治疗显着降低早老蛋白水平，导致救援异染色质组织和重组的转录HGPS成纤维细胞。这些结果表明，HGPS核的形态功能缺陷与早老蛋白的积累直接相关，并且可以通过药物治疗来纠正。
Hutchinson-Gilford progeria (HGPS) is a premature aging syndrome associated with LMNA mutations. Progeria cells bearing the G608G LMNA mutation are characterized by accumulation of a mutated lamin A precursor (progerin), nuclear dysmorphism and chromatin disorganization. In cultured HGPS fibroblasts, we found worsening of the cellular phenotype with patient age, mainly consisting of increased nuclear-shape abnormalities, progerin accumulation and heterochromatin loss. Moreover, transcript distribution was altered in HGPS nuclei, as determined by different techniques. In the attempt to improve the cellular phenotype, we applied treatment with drugs either affecting protein farnesylation or chromatin arrangement. Our results show that the combined treatment with mevinolin and the histone deacetylase inhibitor trichostatin A dramatically lowers progerin levels, leading to rescue of heterochromatin organization and reorganization of transcripts in HGPS fibroblasts. These results suggest that morpho-functional defects of HGPS nuclei are directly related to progerin accumulation and can be rectified by drug treatment.
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影响因子：
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