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

Zhang, Xiaohong; Cook, Peter C.; Zindy, Egor; Williams, Craig J.; Jowitt, Thomas A.; Streuli, Charles; MacDonald, Andrew S.; Redondo-Muñóz, Javier

doi:10.1093/nar/gkv1348

Cited by 42 publications

(37 citation statements)

References 56 publications

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“…It has been suggested that mechanoadaptation of the chromatin occurs faster than nuclear lamina alterations [13,20]. Aligning with these studies, we have previously described that epigenetic changes related with closed chromatin conformation alter the mechanical properties and shape of nuclei from lymphocytes and leukemia cells [21]. Now, we have extended these results and described how increased levels of a euchromatin marker (H3K4 methylation) are linked to the biomechanical properties of isolated nuclei from cells moving in 3D environments [22].…”

Section: Chromatin Contribution To Nuclear Stiffnesssupporting

confidence: 61%

Novel contribution of epigenetic changes to nuclear dynamics

Dreger

Madrazo

Hurlstone

et al. 2019

Nucleus

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Migrating cells have to cross many physical barriers and confined in 3D environments. The surrounding environment promotes mechano- and biological signals that orchestrate cellular changes, such as cytoskeletal and adhesion rearrangements and proteolytic digestion. Recent studies provide new insights into how the nucleus must alter its shape, localization and mechanical properties in order to promote nuclear deformability, chromatin compaction and gene reprogramming. It is known that the chromatin structure contributes directly to genomic and non-genomic functions, such as gene transcription and the physical properties of the nucleus. Here, we appraise paradigms and novel insights regarding the functional role of chromatin during nuclear deformation. In so doing, we review how constraint and mechanical conditions influence the structure, localization and chromatin decompaction. Finally, we highlight the emerging roles of mechanogenomics and the molecular basis of nucleoskeletal components, which open unexplored territory to understand how cells regulate their chromatin and modify the nucleus.

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Section: Chromatin Contribution To Nuclear Stiffnesssupporting

confidence: 61%

Novel contribution of epigenetic changes to nuclear dynamics

Dreger

Madrazo

Hurlstone

et al. 2019

Nucleus

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“…Previous studies on various integrins highlight that, in addition to adhesion, these receptors regulate cell migration, proliferation, cell-fate determination, cell cycle progression, apoptosis prevention, and cell survival and differentiation in diverse cell types (71)(72)(73)(74)(75)(76)(77). Binding of activated integrins to their ligands results in a number of signaling, structural, and phenotypic changes within the cell.…”

Section: Integrin's Functions Beyond Cell Adhesionmentioning

confidence: 99%

“…Several multiprotein complexes assemble onto integrins' cytoplasmic tails to engage and reorganize the cytoskeletal systems, as well as to facilitate the transmission of signaling cascades that ultimately lead to changes in the expression of certain genes. For example, VLA-4 regulates G9a activity that controls epigenetic changes and the nuclear properties that are required for lymphocyte migration (73). In mammary epithelium, b 1 integrin plays a major role in controlling differentiation and development, as well as in the cellular programming of epithelial functions (74,75).…”

Section: Integrin's Functions Beyond Cell Adhesionmentioning

confidence: 99%

Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program

Verma

Kelleher

2017

The Journal of Immunology

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The αβ integrin LFA-1 is known to play a key role in T lymphocyte migration, which is necessary to mount a local immune response, and is also the main driver of autoimmune diseases. This migration-triggering signaling process in T cells is tightly regulated to permit an immune response that is appropriate to the local trigger, as well as to prevent deleterious tissue-damaging bystander effects. Emerging evidence shows that, in addition to prompting a diverse range of downstream signaling cascades, LFA-1 stimulation in T lymphocytes modulates gene-transcription programs, including genetic signatures of TGF-β and Notch pathways, with multifactorial biological outcomes. This review highlights recent findings and discusses molecular mechanisms by which LFA-1 signaling influence T lymphocyte differentiation into the effector subsets Th1, Th17, and induced regulatory T cells. We argue that LFA-1 contact with a cognate ligand, such as ICAM-1, independent of the immune synapse activates a late divergence in T cells' effector phenotypes, hence fine-tuning their functioning.

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“…Epigenetic modifications, which include covalent changes in histones and DNA, regulate chromatin structure and gene expression (12). Some histone markers have been related to cancer progression and cell migration (13)(14)(15). The histone H3 is methylated at the residue K4 by specific methyltransferase complexes, which comprise a catalytic subunit (SET/MLL) and several core scaffolding subunits, including WDR5 (WD repeat-containing protein 5), ASH2L, RbBP5, and mDPY-30 (16).…”

Section: Introductionmentioning

confidence: 99%

WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment

Wang

Dreger

Madrazo

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Abstract:Cell migration through extracellular matrices requires nuclear deformation, which depends on nuclear stiffness. In turn, chromatin structure contributes to nuclear stiffness, but the mechanosensing pathways regulating chromatin during cell migration remain unclear. Here, we demonstrate that WD repeat domain 5 (WDR5), an essential component of H3K4 methyltransferase complexes, regulates cell polarity, nuclear deformability and migration of lymphocytes in vitro and in vivo, independent of transcriptional activity, suggesting non-genomic functions for WDR5. Similarly, depletion of RbBP5 (another H3K4 methyltransferase subunit) promotes similar defects. We reveal that a 3D environment increases the H3K4 methylation dependent on WDR5, and results in a globally less compacted chromatin conformation. Further, using atomic force microscopy, nuclear particle tracking and nuclear swelling experiments, we detect changes in nuclear mechanics that accompany the epigenetic changes induced in 3D conditions. Indeed, nuclei from cells in 3D environments were softer, and thereby more deformable, compared to cells in suspension or cultured in 2D conditions, again dependent on WDR5. Dissecting the underlying mechanism, we determined that actomyosin contractility, through the phosphorylation of myosin by MLCK (myosin light chain kinase), controls the interaction of WDR5 with other components of the methyltransferase complex, which in turn upregulates H3K4 methylation activation in 3D conditions. Taken together, our findings reveal a novel non-genomic function for WDR5 in regulating H3K4 methylation induced by 3D environments, physical properties of the nucleus, cell polarity and cell migratory capacity. 3 Significance:Cells require nuclear deformation to squeeze through tissue matrices. We have discovered that WDR5 (an epigenetic modulator of H3K4 methylation) is fundamental for cell polarity and migration in vitro and in vivo, independently of transcription. We have uncovered that the interactions between cells and the surrounding 3D confined conditions induce the upregulation of H3K4me3. Moreover, 3D environments control the deformability and the mechanical properties of the nucleus. We have identified that loss of WDR5 abrogates the H3K4 methylation and the nuclear changes induced by 3D conditions. Mechanistically, we found that MLCK and myosin function was required for WDR5-mediated H3K4 methylation in 3D matrices. Our findings uncover new functions of the epigenetic machinery when cells move through constricted conditions.

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

Cited by 42 publications

References 56 publications

Novel contribution of epigenetic changes to nuclear dynamics

Novel contribution of epigenetic changes to nuclear dynamics

Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program

WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment

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