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Nuclear retention of importin ? coordinates cell fate through changes in gene expression.

ABSTRACT: Various cellular stresses including oxidative stress induce a collapse of the Ran gradient, which causes accumulation of importin ? in the nucleus and a subsequent block of nuclear protein import. However, it is unknown whether accumulated importin ? performs roles in the nucleus after its migration in response to stress. In this study, we found that nuclear-retained importin ?2 binds with DNase I-sensitive nuclear component(s) and exhibits selective upregulation of mRNA encoding Serine/threonine kinase 35 (STK35) by microarray analysis. Chromatin immunoprecipitation and promoter analysis demonstrated that importin ?2 can access to the promoter region of STK35 and accelerate its transcription in response to hydrogen peroxide exposure. Furthermore, constitutive overexpression of STK35 proteins enhances caspase-independent cell death under oxidative stress conditions. These results collectively reveal that nuclear-localized importin ?2 influences gene expression and contributes directly to cell fate outcomes including non-apoptotic cell death.

SUBMITTER: Yasuda Y

PROVIDER: S-EPMC3252573 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Nuclear retention of importin α coordinates cell fate through changes in gene expression.

Yasuda Yoshinari Y Miyamoto Yoichi Y Yamashiro Tomoko T Asally Munehiro M Masui Ayumi A Wong Chin C Loveland Kate L KL Yoneda Yoshihiro Y

The EMBO journal 20110930 1

Various cellular stresses including oxidative stress induce a collapse of the Ran gradient, which causes accumulation of importin α in the nucleus and a subsequent block of nuclear protein import. However, it is unknown whether accumulated importin α performs roles in the nucleus after its migration in response to stress. In this study, we found that nuclear-retained importin α2 binds with DNase I-sensitive nuclear component(s) and exhibits selective upregulation of mRNA encoding Serine/threonin ...[more]

PMID: 21964068

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Project description:BackgroundA fundamental issue in bioscience is to understand the mechanism that underlies the dynamic control of genome-wide expression through the complex temporal-spatial self-organization of the genome to regulate the change in cell fate. We address this issue by elucidating a physically motivated mechanism of self-organization.Principal findingsBuilding upon transcriptome experimental data for seven distinct cell fates, including early embryonic development, we demonstrate that self-organized criticality (SOC) plays an essential role in the dynamic control of global gene expression regulation at both the population and single-cell levels. The novel findings are as follows: i) Mechanism of cell-fate changes: A sandpile-type critical transition self-organizes overall expression into a few transcription response domains (critical states). A cell-fate change occurs by means of a dissipative pulse-like global perturbation in self-organization through the erasure of initial-state critical behaviors (criticality). Most notably, the reprogramming of early embryo cells destroys the zygote SOC control to initiate self-organization in the new embryonal genome, which passes through a stochastic overall expression pattern. ii) Mechanism of perturbation of SOC controls: Global perturbations in self-organization involve the temporal regulation of critical states. Quantitative evaluation of this perturbation in terminal cell fates reveals that dynamic interactions between critical states determine the critical-state coherent regulation. The occurrence of a temporal change in criticality perturbs this between-states interaction, which directly affects the entire genomic system. Surprisingly, a sub-critical state, corresponding to an ensemble of genes that shows only marginal changes in expression and consequently are considered to be devoid of any interest, plays an essential role in generating a global perturbation in self-organization directed toward the cell-fate change.Conclusion and significance'Whole-genome' regulation of gene expression through self-regulatory SOC control complements gene-by-gene fine tuning and represents a still largely unexplored non-equilibrium statistical mechanism that is responsible for the massive reprogramming of genome expression.

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Nuclear retention of importin ? coordinates cell fate through changes in gene expression.

Publications

Nuclear retention of importin α coordinates cell fate through changes in gene expression.

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