Historic acetylation in vivo at the osteocalcin locus is functionally linked to vitamin D-dependent, bone tissue-specific transcription.
Historic acetylation in vivo at the osteocalcin locus is functionally linked to vitamin D-dependent, bone tissue-specific transcription.
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DOI：
10.1074/jbc.m112440200
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发表时间：
2002-06-07
影响因子：
4.8
通讯作者：
Stein, JL
中科院分区：
文献类型：
--
作者：
Shen, JL;Montecino, M;Stein, JL
染色质中调控元件的可及性代表了基因转录的主要限速参数，并由改变染色质拓扑结构或共价修饰组蛋白的酶促转录辅助因子调节（例如通过乙酰化）。骨钙素（OC）基因转录的骨特异性激活和1,25-二羟基维生素D-3增强都与核小体组织的修饰在功能上相关。组织特异性基础转录的启动伴随着两个DNase I超敏感位点的诱导，这一染色质重塑事件需要将关键成骨因子RUNX2/CBFA1结合到OC启动子上。在这里，我们使用染色质免疫沉淀法分析了OC基因激活（成骨细胞ROS17/2.8细胞）或不活跃（成纤维细胞ROS24/1细胞）时组蛋白H3和H4的乙酰化状态。我们发现乙酰化组蛋白H3和H4蛋白仅在基因转录活跃时才与OC启动子相关，并且在基础条件下OC位点的乙酰化状态相对统一。维生素D3增强OC转录后，OC基因上H4的乙酰化选择性增加，其中最显著的变化发生在维生素D3增强子和基础启动子之间的区域。因此，我们的研究结果表明，OC启动子特定区域的H3和H4乙酰化与染色质重塑的功能联系，伴随着组织特异性转录激活和维生素D增强OC基因表达。这些发现提供了在原生基因组背景下响应类固醇激素相关调控线索的骨特异性基因激活的机制见解。
The accessibility of regulatory elements in chromatin represents a principal rate-limiting parameter of gene transcription and is modulated by enzymatic transcriptional co-factors that alter the topology of chromatin or covalently modify histones (e.g. by acetylation). The bone-specific activation and 1,25-dihydroxyvitamin D-3 enhancement of osteocalcin (OC) gene transcription are both functionally linked to modifications in nucleosomal organization. The initiation of tissue-specific basal transcription is accompanied by the induction of two DNase I hypersensitive sites, and this chromatin remodeling event requires binding of the key osteogenic factor RUNX2/CBFA1 to the OC promoter. Here, we analyzed the acetylation status of histones H3 and H4 when the OC gene is active (in osteoblastic ROS17/2.8 cells) or inactive (in fibroblastic ROS24/1 cells) using chromatin immunoprecipitation assays. We find that acetylated histone H3 and H4 proteins are associated with the OC promoter only when the gene is transcriptionally active and that the acetylation status is relatively uniform across the OC locus under basal conditions. Acetylation of H4 at the OC gene is selectively increased following vitamin D3 enhancement of OC transcription, with the most prominent changes occurring in the region between the vitamin D3 enhancer and basal promoter. Thus, our results suggest functional linkage of H3 and H4 acetylation in specific regions of the OC promoter to chromatin remodeling that accompanies tissue-specific transcriptional activation and vitamin D enhancement of OC gene expression. These findings provide mechanistic insights into bone-specific gene activation within a native genomic context in response to steroid hormone-related regulatory cues.