title: Integrin α4β1 controls G9a activity that regulates epigenetic changes and nuclear properties required for lymphocyte migration.
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.
authors.affiliation: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, M13 9NT, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Cook
authors.affiliation: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Egor
authors.initials: E
authors.lastname: Zindy
authors.affiliation: Materials Science Centre, School of Materials, University of Manchester, Manchester, M13 9PL, UK.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Williams
authors.affiliation: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jowitt
authors.affiliation: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Streuli
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, M13 9NT, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: MacDonald
authors.affiliation: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK Javier.redondo-munoz@manchester.ac.uk.
authors.forename: Javier
authors.initials: J
authors.lastname: Redondo-Muñoz
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006649:Histocompatibility Antigens / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D019169:Jurkat Cells; D008214:Lymphocytes / Q000276:immunology*; D008745:Methylation; D008810:Mice, Inbred C57BL; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D002843:Chromatin; D006649:Histocompatibility Antigens; D006657:Histones; D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1; C445405:EHMT2 protein, human; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase