Integrin α4β1 controls G9a activity that regulates epigenetic changes and nuclear properties required for lymphocyte migration.

Xiaohong Zhang, Peter Cook, Egor Zindy, Will Williams, Thomas Jowitt, Charles Streuli, Andrew MacDonald, Javier Redondo-Munoz

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The mechanical properties of the cell nucleus change to allow cells to migrate, but how chromatin modifications contribute to nuclear deformability has not been defined. Here, we demonstrate that a major factor in this process involves epigenetic changes that underpin nuclear structure. We investigated the link between cell adhesion and epigenetic changes in T-cells, and demonstrate that T-cell adhesion to VCAM1 via α4β1 integrin drives histone H3 methylation (H3K9me2/3) through the methyltransferase G9a. In this process, active G9a is recruited to the nuclear envelope and interacts with lamin B1 during T-cell adhesion through α4β1 integrin. G9a activity not only reorganises the chromatin structure in T-cells, but also affects the stiffness and viscoelastic properties of the nucleus. Moreover, we further demonstrated that these epigenetic changes were linked to lymphocyte movement, as depletion or inhibition of G9a blocks T-cell migration in both 2D and 3D environments. Thus, our results identify a novel mechanism in T-cells by which α4β1 integrin signaling drives specific chromatin modifications, which alter the physical properties of the nucleus and thereby enable T-cell migration.
    Original languageEnglish
    Pages (from-to)3031-3044
    Number of pages4
    JournalNucleic acids research
    Volume44
    Issue number7
    Early online date10 Dec 2015
    DOIs
    Publication statusPublished - 20 Apr 2016

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