Transcription initiation patterns indicate divergent strategies for gene regulation at the chromatin level.
Transcription initiation patterns indicate divergent strategies for gene regulation at the chromatin level.
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DOI：
10.1371/journal.pgen.1001274
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发表时间：
2011-01-13
期刊：
影响因子：
4.5
通讯作者：
Ohler U
中科院分区：
文献类型：
--
作者：
Rach EA;Winter DR;Benjamin AM;Corcoran DL;Ni T;Zhu J;Ohler U
应用深度测序绘制5′加帽转录物已经证实了多细胞动物中至少存在两种不同的启动子类型：具有转录起始位点（TSS）的“集中”启动子，其出现在狭窄的基因组跨度中，以及具有TSS的“分散”启动子，其分布在更大的窗口中。以前的研究已经探索了基因组特征的存在，如CpG岛和序列基序，在这些启动子类，但几乎没有研究直接调查与染色质特征的关系。在这里，我们表明，启动子类显着分化的核小体组织和染色质结构。分散的启动子显示出与TSS下游定位良好的核小体和上游更明确的无核小体区域的更高关联，而集中的启动子具有组织化程度较低的核小体结构，但RNA聚合酶II的存在较高。这些差异延伸到组蛋白变体（H2A.Z）和标记（H3K4甲基化），以及绝缘子结合（如CTCF），与受影响基因的表达水平无关。值得注意的是，差异在哺乳动物和果蝇中是保守的，并且它们提供了比CpG岛的存在和不存在或停滞的RNA聚合酶的出现更清楚的启动子结构分离。计算模型支持较强的贡献染色质功能的定义分散的启动子相比，集中的起始位点。我们的研究结果表明，从5′加帽的转录本定义的启动子类别不仅反映了在核心启动子的起始过程的差异，但也表明不同的转录程序建立在基因近端核小体组织。基因是如何在正确的水平和条件下转录的？真核生物中的转录调控长期以来一直被认为是通过分工来进行的：核心启动子区域中的普遍存在的DNA序列特征，靠近基因的转录起始位点（TSS），被认为是一般编码信息以招募RNA聚合酶来启动转录，而通常远离基因的特定序列特征被认为是在正确的条件下促进表达。支持核心启动子的通用功能，全基因组染色质图谱显示了间距良好的核小体的定型排列，提供了进入TSS的途径。高通量测序已经产生了高分辨率的全基因组TSS图谱，这表明启动子表现出不同的起始模式，从集中的起始位点到分散的区域。将这些模式与染色质图谱联系起来，我们现在发现了不同的核心启动子类别，其中TSS位置在染色质水平上广泛定义，而TSS由精确定位的序列特征定义。值得注意的是，这些结构在真核生物中高度保守，并用于不同功能类别的基因。我们的工作增加了对核心启动子对真核基因表达复杂性的重要贡献的理解。
The application of deep sequencing to map 5′ capped transcripts has confirmed the existence of at least two distinct promoter classes in metazoans: “focused” promoters with transcription start sites (TSSs) that occur in a narrowly defined genomic span and “dispersed” promoters with TSSs that are spread over a larger window. Previous studies have explored the presence of genomic features, such as CpG islands and sequence motifs, in these promoter classes, but virtually no studies have directly investigated the relationship with chromatin features. Here, we show that promoter classes are significantly differentiated by nucleosome organization and chromatin structure. Dispersed promoters display higher associations with well-positioned nucleosomes downstream of the TSS and a more clearly defined nucleosome free region upstream, while focused promoters have a less organized nucleosome structure, yet higher presence of RNA polymerase II. These differences extend to histone variants (H2A.Z) and marks (H3K4 methylation), as well as insulator binding (such as CTCF), independent of the expression levels of affected genes. Notably, differences are conserved across mammals and flies, and they provide for a clearer separation of promoter architectures than the presence and absence of CpG islands or the occurrence of stalled RNA polymerase. Computational models support the stronger contribution of chromatin features to the definition of dispersed promoters compared to focused start sites. Our results show that promoter classes defined from 5′ capped transcripts not only reflect differences in the initiation process at the core promoter but also are indicative of divergent transcriptional programs established within gene-proximal nucleosome organization. How are genes transcribed at the right levels and under the right conditions? Transcription regulation in eukaryotes has long been proposed to work by a division of labor: ubiquitous DNA sequence features in the core promoter region, close to the transcription start site (TSS) of genes, were thought to generically encode information to recruit RNA polymerase to initiate transcription, while specific sequence features, often distal from the genes, were thought to boost expression under the right conditions. Supporting the generic function of core promoters, genome-wide chromatin maps showed a stereotypical arrangement of well-spaced nucleosomes providing access to the TSS. High-throughput sequencing has generated genome-wide TSS maps at high resolution, which show that promoters exhibit different initiation patterns, ranging from focused start sites to dispersed regions. Linking these patterns to chromatin maps, we now find distinct core promoter classes, those in which the TSS location is defined broadly on the chromatin level and those in which the TSS is defined by precisely positioned sequence features. Notably, these architectures are conserved deeply across eukaryotes and are used for different functional classes of genes. Our work adds to the increasing understanding that core promoters contribute significantly to the complexity of eukaryotic gene expression.
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