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Nat Immunol. 2015 May;16(5):505-16. doi: 10.1038/ni.3125. Epub 2015 Mar 9.

The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin.

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School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
Department of immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
1] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore. [2] Institute of Molecular &Cell Biology, Agency for Science and Technology Research, Republic of Singapore.
Department of Medicine, University of California San Diego, La Jolla, California, USA.


A cytosolic role for the histone methyltransferase Ezh2 in regulating lymphocyte activation has been suggested, but the molecular mechanisms underpinning this extranuclear function have remained unclear. Here we found that Ezh2 regulated the integrin signaling and adhesion dynamics of neutrophils and dendritic cells (DCs). Ezh2 deficiency impaired the integrin-dependent transendothelial migration of innate leukocytes and restricted disease progression in an animal model of multiple sclerosis. Direct methylation of talin, a key regulatory molecule in cell migration, by Ezh2 disrupted the binding of talin to F-actin and thereby promoted the turnover of adhesion structures. This regulatory effect was abolished by targeted disruption of the interactions of Ezh2 with the cytoskeletal-reorganization effector Vav1. Our studies reveal an unforeseen extranuclear function for Ezh2 in regulating adhesion dynamics, with implications for leukocyte migration, immune responses and potentially pathogenic processes.

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