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WIREs Syst Biol Med
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Advances in analysis of transcriptional regulatory networks

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Abstract A transcriptional regulatory network represents a molecular framework in which developmental or environmental cues are transformed into differential expression of genes. Transcriptional regulation is mediated by the combinatorial interplay between cis‐regulatory DNA elements and trans‐acting transcription factors, and is perhaps the most important mechanism for controlling gene expression. Recent innovations, most notably the method for detecting protein–DNA interactions genome‐wide, can help provide a comprehensive catalog of cis‐regulatory elements and their interaction with given trans‐acting factors in a given condition. A transcriptional regulatory network that integrates such information can lead to a systems‐level understanding of regulatory mechanisms. In this review, we will highlight the key aspects of current knowledge on eukaryotic transcriptional regulation, especially on known transcription factors and their interacting regulatory elements. Then we will review some recent technical advances for genome‐wide mapping of DNA–protein interactions based on high‐throughput sequencing. Finally, we will discuss the types of biological insights that can be obtained from a network‐level understanding of transcription regulation as well as future challenges in the field. WIREs Syst Biol Med 2011 3 21–35 DOI:10.1002/wsbm.105 This article is categorized under: Analytical and Computational Methods > Analytical Methods Laboratory Methods and Technologies > Macromolecular Interactions, Methods Biological Mechanisms > Regulatory Biology

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A composite model of cis‐regulatory elements. Key cis‐regulatory elements are shown. The core promoters directly upstream of TSS bind the general transcriptional machinery (TATA and INR; refer to the TATA box and the initiator sequence, respectively); proximal promoters bind cognate sequence‐specific transcription factors (shown as trapezoids). Distal enhancers and silencer elements also provide binding sites for sequence‐specific transcription factors, but have opposite regulatory effects on the transcription activity of regulated genes. In some cases, an enhancer can regulate distant genes, mediated by a DNA‐looping mechanism..

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Examples of network motifs, modules and transcriptional regulatory network. (a) Well‐known network motifs in transcriptional regulatory networks are shown. These are autoregulation, a feed‐forward loop, and single‐ and multiple‐input motifs66 (left to right). The red circles and blue rectangles represent the transcriptional factors (regulators) and their target genes, respectively. (b) An example of modules in a network is shown. The nodes within the modules are highly interconnected with each other. A clustering coefficient can be calculated to measure the extent of connectivity or cliqueness of nodes in a module. (c) A yeast transcription regulatory network was constructed here using 17,873 known relationships between transcription factors and their target genes. The genes were classified into transcription regulators (red circle) and regulated genes (black circle) according to the annotations in the original manuscript.95 The network is visualized using the Cytoscape software with the organic layout option.98.

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Overview of chromatin immunoprecipitation (ChIP)‐chip and ChIP‐seq. (a) Reversible cross‐linking of DNA and protein is performed by treating the DNA–protein complex with formaldehyde. The cross‐linked DNA–protein complex is fragmented by sonication. (b) An antibody specific to the protein of interest is used to enrich the DNA segments bound to the protein. (c) The purified DNA is profiled using a microarray (ChIP‐chip; left) or direct sequencing (ChIP‐seq; right)..

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Modeling of individual transcription factor binding sites and cis‐regulatory modules (CRMs). (a) The position frequency matrix of the c‐Myc binding motif (TRANSFAC matrix index M00118, V$MYCMAX_01) is shown as an example. (b) The cluster of individual transcription factor binding sites is modeled as a CRM. CRMs have a different composition and organization of transcription factor binding sites and can be considered as functional units of cis‐regulation. (c) An example of a regulatory relationship among four genes is shown. Gene A regulates the transcriptional activity of its target gene B and genes A and B together regulate their target genes C and D..

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Analytical and Computational Methods > Analytical Methods
Biological Mechanisms > Regulatory Biology
Laboratory Methods and Technologies > Macromolecular Interactions, Methods

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