Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation

• Published in: Cell Vol. 148; no. 1-2; pp. 84 - 98
• Main Authors: Li, Guoliang, Ruan, Xiaoan, Auerbach, Raymond K., Sandhu, Kuljeet Singh, Zheng, Meizhen, Wang, Ping, Poh, Huay Mei, Goh, Yufen, Lim, Joanne, Zhang, Jingyao, Sim, Hui Shan, Peh, Su Qin, Mulawadi, Fabianus Hendriyan, Ong, Chin Thing, Orlov, Yuriy L., Hong, Shuzhen, Zhang, Zhizhuo, Landt, Steve, Raha, Debasish, Euskirchen, Ghia, Wei, Chia-Lin, Ge, Weihong, Wang, Huaien, Davis, Carrie, Fisher-Aylor, Katherine I., Mortazavi, Ali, Gerstein, Mark, Gingeras, Thomas, Wold, Barbara, Sun, Yi, Fullwood, Melissa J., Cheung, Edwin, Liu, Edison, Sung, Wing-Kin, Snyder, Michael, Ruan, Yijun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2012
• Subjects: Cell Line, Tumor; chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation; DNA-directed RNA polymerase; Enhancer Elements, Genetic; eukaryotic cells; Gene Expression Regulation; genes; Genome-Wide Association Study; Humans; Promoter Regions, Genetic; RNA Polymerase II - metabolism; topology; transcription (genetics); Transcription, Genetic
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2011.12.014

Higher-order chromosomal organization for transcription regulation is poorly understood in eukaryotes. Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing (ChIA-PET), we mapped long-range chromatin interactions associated with RNA polymerase II in human cells and uncovered widespread promoter-centered intragenic, extragenic, and intergenic interactions. These interactions further aggregated into higher-order clusters, wherein proximal and distal genes were engaged through promoter-promoter interactions. Most genes with promoter-promoter interactions were active and transcribed cooperatively, and some interacting promoters could influence each other implying combinatorial complexity of transcriptional controls. Comparative analyses of different cell lines showed that cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription, and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions. Furthermore, genetically-identified disease-associated noncoding elements were found to be spatially engaged with corresponding genes through long-range interactions. Overall, our study provides insights into transcription regulation by three-dimensional chromatin interactions for both housekeeping and cell-specific genes in human cells. [Display omitted] ► Promoter-centered interactions are complex and widespread ► Higher-order chromatin architectures facilitate active and coordinated transcription ► Interacting promoters possess combinatorial regulatory functions ► Large enhancer-promoter repertoire allows functional annotation of noncoding elements Higher order chromatin interactions between promoters synergistically promote transcription of clustered genes. These interactions indicate a topological, combinatorial mechanism of transcriptional and also suggest functions for noncoding elements, including those associated with disease, by connecting them to target genes.