A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes
A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes
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DOI：
10.1096/fj.09-133215
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发表时间：
2009-10-01
期刊：
影响因子：
4.8
通讯作者：
Hall, David J.
中科院分区：
文献类型：
--
作者：
Hong, Sohee;Derfoul, Assia;Hall, David J.
在原代人软骨细胞中探讨了组蛋白脱乙酰酶 1 和 2（HDAC1 和 HDAC2）在调节软骨特异性基因表达中的作用。骨关节炎患者的软骨细胞中 HDAC1 和 HDAC2 蛋白水平升高，这与一些软骨标记基因的下调一致。当在这些细胞中表达时，HDAC1 和 HDAC2 抑制聚集蛋白聚糖和胶原蛋白 2(α 1) 的表达，但对胶原蛋白 9(α 1)、胶原蛋白 11(α 1)、皮桥蛋白和软骨寡聚基质蛋白 (COMP) 的抑制有所不同。为了确定 HDAC1 和 HDAC2 之间差异的基础，删除了它们的羧基末端结构域 (CTD)，这导致蛋白质保留了酶活性，但无法抑制软骨基因表达。此外，HDAC1 和 HDAC2 之间 CTD 的交换导致蛋白质具有酶活性，但显示出改变的靶基因特异性，表明这些 CTD 可以独立于 HDAC 酶活性发挥作用，将 HDAC 靶向特定基因。 Snail 转录因子通过与 HDAC1 和 2 CTD 的相互作用，被确定为 HDAC1 和 HDAC2 抑制胶原蛋白 2(α 1) 基因的介质。数据表明，CTD 在 HDAC1 和 HDAC2 中发挥新功能，介导人类软骨细胞中软骨特异性基因表达的抑制。-Hong, S.、Derfoul, A.、Pereira-Mouries, L.、Hall, D. J. 组蛋白脱乙酰酶 1 和 2 中的一个新结构域介导人类软骨细胞中软骨特异性基因的抑制。 FASEB J. 23, 3539-3552 (2009)。 www.fasebj.org
The role of histone deacetylase 1 and 2 (HDAC1 and HDAC2) in regulating cartilage-specific gene expression was explored in primary human chondrocytes. HDAC1 and HDAC2 protein levels were elevated in chondrocytes from osteoarthritic patients, consistent with a down-regulation of some cartilage marker genes. When expressed in these cells, HDAC1 and HDAC2 repressed aggrecan and collagen 2(alpha 1) expression but differed in their repression of collagen 9(alpha 1), collagen 11(alpha 1), dermatopontin, and cartilage oligomeric matrix protein (COMP). To identify the basis of these differences between HDAC1 and HDAC2, their carboxy-terminal domains (CTDs) were deleted, which led to proteins that retained enzymatic activity but were unable to repress cartilage gene expression. Further, exchange of the CTDs between HDAC1 and HDAC2 led to proteins that were enzymatically active but displayed altered target gene specificity, indicating that these CTDs can function independently of HDAC enzymatic activity, to target the HDACs to specific genes. The Snail transcription factor was identified as a mediator of HDAC1 and HDAC2 repression of the collagen 2(alpha 1) gene, via its interaction with the HDAC1 and 2 CTDs. The data indicate that the CTD serves a novel function within HDAC1 and HDAC2, to mediate repression of cartilage-specific gene expression in human chondrocytes.-Hong, S., Derfoul, A., Pereira-Mouries, L., Hall, D. J. A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes. FASEB J. 23, 3539-3552 (2009). www.fasebj.org