Epigenetic Repression of Matrix Metalloproteinases in Myofibroblastic Hepatic Stellate Cells through Histone Deacetylases 4 Implication in Tissue Fibrosis
Epigenetic Repression of Matrix Metalloproteinases in Myofibroblastic Hepatic Stellate Cells through Histone Deacetylases 4 Implication in Tissue Fibrosis
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DOI：
10.2353/ajpath.2010.100011
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发表时间：
2010-10-01
影响因子：
6
通讯作者：
Han, Yuan-Ping
中科院分区：
文献类型：
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作者：
Qin, Lan;Han, Yuan-Ping
在急性损伤中高度表达的基质金属蛋白酶（MMPs）在纤维化肝中被逐渐抑制或沉默，有利于细胞外基质的积累，但其潜在机制在很大程度上尚不清楚。同样，正常/静止的肝星状细胞（hsc）在响应损伤信号（如白细胞介素-1）时表达高水平的MMPs。转分化后，肌成纤维hsc不能表达许多MMPs；然而，MMP表达所需的主要信号通路是完整的，这表明抑制在染色质水平上。事实上，转录因子和RNA聚合酶II都无法进入MMP9和MMP13基因，这与它们的启动子中组蛋白乙酰化受损有关。与细胞水平组蛋白乙酰化受损一致，组蛋白去乙酰酶-4在HSC转分化过程中积累。此外，静止hsc中组蛋白去乙酰酶-4的异位表达导致MMP启动子活性和内源性MMP9蛋白表达的抑制。因此，我们的研究结果表明，在组织纤维化过程中，一种依赖于组蛋白去乙酰酶-4的机制是MMP基因表观遗传沉默的基础。（中华病理学杂志，2010,17:1915-1928;10.2353/ajpath.2010.100011）
Matrix metalloproteinases (MMPs), which are highly expressed in acute injury, are progressively repressed or silenced in fibrotic liver, favoring extracellular matrix accumulation, while the underlying mechanism is largely unknown. Similarly, normal/quiescent hepatic stellate cells (HSCs) express high levels of MMPs in response to injury signals, such as interleukin-1. After transdifferentiation, the myofibroblastic HSCs are incapable of expressing many MMPs; however, the major signaling pathways required for MMP expression are intact, indicating that repression is at the level of the chromatin. Indeed, both the MMP9 and MMP13 genes are inaccessible to transcription factors and RNA polymerase II, in association with impaired histone acetylation in their promoters. In accordance with impaired histone acetylation at the cellular level, histone deacetylase-4 is accumulated during HSC transdifferentiation. Furthermore, ectopic expression of histone deacetylase-4 in quiescent HSCs results in repression of MMP promoter activities as well as endogenous MMP9 protein expression. Thus, our findings suggest that a histone deacetylase-4-dependent mechanism underlies the epigenetic silencing of MMP genes during tissue fibrogenesis. (Am J Pathol 2010, 177:1915-1928; 10.2353/ajpath.2010.100011)