Systematic analysis of posttranscriptional gene expression

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Adam R. Morris, Neelanjan Mukherjee, Jack D. Keene

Published Online: Aug 14 2009

DOI: 10.1002/wsbm.54

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Recent systems studies of gene expression have begun to dissect the layers of regulation that underlie the eukaryotic transcriptome, the combined consequence of transcriptional and posttranscriptional events. Among the regulatory layers of the transcriptome are those of the ribonome, a highly dynamic environment of ribonucleoproteins in which RNA‐binding proteins (RBPs), noncoding regulatory RNAs (ncRNAs) and messenger RNAs (mRNAs) interact. While multiple mRNAs are coordinated together in groups within the ribonome of a eukaryotic cell, each individual type of mRNA consists of multiple copies, each of which has an opportunity to be a member of more than one modular group termed a posttranscriptional RNA operon or regulon (PTRO). The mRNAs associated with each PTRO encode functionally related proteins and are coordinated at the levels of RNA stability and translation by the actions of the specific RBPs and noncoding regulatory RNAs. This article examines the methods that led to the elucidation of PTROs and the coordinating mechanisms that appear to regulate the RNA components of PTROs. Moreover, the article considers the characteristics of the dynamic systems that drive PTROs and how mRNA components are bound collectively in physical ‘states’ to respond to cellular perturbations and diseases. In conclusion, these studies have challenged the extent to which cellular mRNA abundance can inform investigators of the functional status of a biological system. We argue that understanding the ribonome has greater potential for illuminating the underlying coordination principles of growth, differentiation, and disease. Copyright © 2009 John Wiley & Sons, Inc.

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Figure 1.

Coordination of posttranscriptional regulation. New transcripts (squiggled lines) emerge from chromosomal DNA and undergo multiple interconnected steps of regulation from splicing through translation. RBPs coordinately regulate functionally related sub‐populations of mRNAs existing in the same state as depicted within different colored shapes, each representing a unique combination of trans‐acting factors (e.g., RBPs and microRNAs). The dotted lines depict the ‘regulators of regulators’ concept presented in the text.

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Figure 2.

Ribonomics overview. Tissues or cells are lysed with conditions optimized to preserve in vivo RNP complexes (triangle‐RNA inscribed in a circle protein inscribed in a square complex). RNPs of interest are immunopurified with an antibody to a specific RBP component. In parallel, a mock IP is performed as a control. Proteins (circle) and mRNAs or microRNAs (triangle) enriched versus the mock immunopurification are detected using proteomics and/or microarray or high‐throughput sequencing.

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Figure 3.

mRNA state dynamics. Depicted are the multiple states of a given type of mRNA (S_{1, 2, …, n}) defined by association with specific RBPs (different colored circles represent different RBPs). RBP–mRNA association and therefore mRNA states can change over time in response to the environment, resulting in the activation/repression of different functional modules (different colored rectangles—f_{1, 2, …, n}), thereby, yielding different phenotypic consequences that vary with cellular conditions (C_{1, 2, …, n}). These consequences are due to changes in the proportion of the mRNA (black triangles) existing in a given state, even though the total copy number for that mRNA species (m_{y, z, …, n}) remains constant across biological conditions.

[ Normal View 52K | Magnified View 87K ]

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