Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity
Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity
复制标题
DOI：
10.1101/gr.121541.111
复制
发表时间：
2011-10-01
期刊：
影响因子：
7
通讯作者：
Furey, Terrence S.
中科院分区：
文献类型：
--
作者：
Song, Lingyun;Zhang, Zhancheng;Furey, Terrence S.
人体包含数千种独特的细胞类型，每一种都具有特殊的功能。细胞特性在很大程度上是由基因转录程序决定的，基因转录程序是由DNA中编码的调控元件决定的。为了确定在代表不同人类细胞类型的七种细胞系中活跃的调控元件，我们使用了DNase-seq和FIRE-seq(甲醛辅助的调节元件分离)来定位“开放染色质”。在七个细胞系中发现了超过87万个DNaseI或FIRE位点，它们与核小体缺失区域紧密对应，覆盖了近9%的基因组。根据与同一细胞中确定的转录因子结合位置的一致性判断，在识别可能的调控元件方面，DNaseI和FIRE的组合比单独使用这两种方法都更有效。所有七种细胞共有的开放染色质往往位于转录起始点或附近，并与CTCF结合位点重合，而只有一种细胞类型的开放染色质位点通常位于远离转录起始点的位置，并含有被细胞类型识别的调控因子识别的DNA基序。我们表明，CTCF结合的开放染色质区域是有效的绝缘体。我们确定了开放调控元件(核心)的簇，这些元件在物理上彼此接近，其外观在一种或多种细胞类型之间是协调的。基因表达和RNA POLII结合数据支持核心控制维持细胞类型特性所需的基因活性的假设。这份公开的调控元件图谱可能被证明在识别与人类疾病有因果联系的非编码DNA序列变体方面有价值。
The human body contains thousands of unique cell types, each with specialized functions. Cell identity is governed in large part by gene transcription programs, which are determined by regulatory elements encoded in DNA. To identify regulatory elements active in seven cell lines representative of diverse human cell types, we used DNase-seq and FAIRE-seq (Formaldehyde Assisted Isolation of Regulatory Elements) to map "open chromatin.'' Over 870,000 DNaseI or FAIRE sites, which correspond tightly to nucleosome-depleted regions, were identified across the seven cell lines, covering nearly 9% of the genome. The combination of DNaseI and FAIRE is more effective than either assay alone in identifying likely regulatory elements, as judged by coincidence with transcription factor binding locations determined in the same cells. Open chromatin common to all seven cell types tended to be at or near transcription start sites and to be coincident with CTCF binding sites, while open chromatin sites found in only one cell type were typically located away from transcription start sites and contained DNA motifs recognized by regulators of cell-type identity. We show that open chromatin regions bound by CTCF are potent insulators. We identified clusters of open regulatory elements (COREs) that were physically near each other and whose appearance was coordinated among one or more cell types. Gene expression and RNA Pol II binding data support the hypothesis that COREs control gene activity required for the maintenance of cell-type identity. This publicly available atlas of regulatory elements may prove valuable in identifying noncoding DNA sequence variants that are causally linked to human disease.