Journal Article

Architecture of the human regulatory network derived from ENCODE data

Mu, Xinmeng Jasmine, Min, Renqiang, Wu, Linfeng, Yip, Kevin Y., Alves, Pedro, Jain, Preti, Charos, Alexandra, Euskirchen, Ghia, Lacroute, Phil, Batzoglou, Serafim, Ouyang, Zhengqing, Cayting, Philip, Hariharan, Manoj, Kundaje, Anshul, Gertz, Jason, Gerstein, Mark B., O’Geen, Henriette, Rozowsky, Joel, Lian, Jin, Alexander, Roger, Shi, Minyi, Snyder, Michael, Zilberman-Schapira, Gili, Yan, Koon-Kiu, Yang, Xinqiong, Reed, Brian, Weissman, Sherman M., Eastman, Catharine, Abyzov, Alexej, Monahan, Hannah, Kasowski, Maya, Pauli, Florencia, Sidow, Arend, Cheng, Yong, Khurana, Ekta, Bhardwaj, Nitin, Boyle, Alan P., Clarke, Declan, Fu, Yao, Patacsil, Dorrelyn, Ramirez, Lucia, Raha, Debasish, Farnham, Peggy J., Landt, Stephen G., Reddy, Timothy E., Cheng, Chao, Slifer, Teri, Frietze, Seth, Wang, Jing, Chen, David Z., Addleman, Nick, Partridge, E. Christopher, Grubert, Fabian, Leng, Jing, Harmanci, Arif, Myers, Richard M.

2012

Overview

Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease. A description is given of the ENCODE consortium’s efforts to examine the principles of human transcriptional regulatory networks; the results are integrated with other genomic information to form a hierarchical meta-network where different levels have distinct properties. ENCODE: architecture of the human regulatory network This manuscript describes the effort of the ENCODE (Encyclopedia of DNA Elements) Consortium to examine the principles of human transcriptional regulatory networks, using a subset of 119 transcription factors. The results are integrated with other genomic information to form a multi-level meta-network in which different levels have distinct properties. The findings will aid future interpretations of human genomics and help us to understand the basic principles of human biology and disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/212 / 631/337/475/2290 / 631/553/2711 / Alleles / Allelomorphism / Binding / Binding sites / Biological and medical sciences / Biology / Cell Line / Combinatorial analysis / Control / Data processing / DNA - genetics / DNA binding proteins / Encyclopedias as Topic / Fundamental and applied biological sciences. Psychology / GATA1 Transcription Factor - metabolism / Gene Expression Profiling / Gene Regulatory Networks - genetics / Genes / Genetic aspects / Genetic regulation / Genetics / Genome, Human - genetics / Genomes / Genomics / Hierarchies / Human / Humanities and Social Sciences / Humans / K562 Cells / Molecular and cellular biology / Molecular genetics / Molecular Sequence Annotation / multidisciplinary / Networks / Organ Specificity / Phosphorylation - genetics / Polymorphism, Single Nucleotide - genetics / Protein Interaction Maps / Protein-protein interactions / Proteins / Regulatory Sequences, Nucleic Acid - genetics / RNA, Untranslated - genetics / RNA, Untranslated - metabolism / Science / Science (multidisciplinary) / Selection, Genetic - genetics / Transcription factors / Transcription Factors - metabolism / Transcription Initiation Site / Transcription. Transcription factor. Splicing. Rna processing