FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription
FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription
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DOI：
10.1016/j.cell.2008.01.018
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发表时间：
2008-03-21
期刊：
影响因子：
64.5
通讯作者：
Brown, Myles
中科院分区：
文献类型：
--
作者：
Lupien, Mathieu;Eeckhoute, Jerome;Brown, Myles
复杂的生物体需要特定于组织的转录程序，但人们对这些程序是如何建立的知之甚少。转录因子FoxA1被认为通过作为与核小体DNA结合的先驱因子而对基因调控做出贡献。通过全基因组的位置分析，我们证明了FoxA1细胞类型的特定功能主要依赖于染色质的差异募集，主要是在远端增强子而不是近端启动子。这种不同的招募导致染色质结构的细胞类型特异性变化，以及与谱系特异性转录因子的功能协作。尽管FoxA1具有结合核小体的能力，但其与染色质位置的差异结合取决于组蛋白H3赖氨酸4二甲基化的分布。综上所述，我们的结果表明，组蛋白H3赖氨酸4的甲基化是表观遗传特征的一部分，该特征定义了染色质中的谱系特异性FoxA1招募位点。FOXA1将这种表观遗传特征转化为染色质结构的变化，从而建立了谱系特异性的转录增强子和程序。
Complex organisms require tissue-specific transcriptional programs, yet little is known about how these are established. The transcription factor FoxA1 is thought to contribute to gene regulation through its ability to act as a pioneer factor binding to nucleosomal DNA. Through genome-wide positional analyses, we demonstrate that FoxA1 cell type-specific functions rely primarily on differential recruitment to chromatin predominantly at distant enhancers rather than proximal promoters. This differential recruitment leads to cell type-specific changes in chromatin structure and functional collaboration with lineage-specific transcription factors. Despite the ability of FoxA1 to bind nucleosomes, its differential binding to chromatin sites is dependent on the distribution of histone H3 lysine 4 dimethylation. Together, our results suggest that methylation of histone H3 lysine 4 is part of the epigenetic signature that defines lineage-specific FoxA1 recruitment sites in chromatin. FoxA1 translates this epigenetic signature into changes in chromatin structure thereby establishing lineage-specific transcriptional enhancers and programs.