Chromatin organization regulated by EZH2-mediated H3K27me3 is required for OPN-induced migration of bone marrow-derived mesenchymal stem cells

• Published in: The international journal of biochemistry & cell biology Vol. 96; pp. 29 - 39
• Main Authors: Liu, Lingling, Luo, Qing, Sun, Jinghui, Ju, Yang, Morita, Yasuyuki, Song, Guanbin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.03.2018
• Subjects: Animals; atomic force microscopy; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Bone marrow-derived mesenchymal stem cells (BMSCs); Cell Movement; Chromatin; Chromatin - metabolism; Chromatin Assembly and Disassembly; Enhancer of Zeste Homolog 2 Protein - metabolism; ERK1/2 signalling; heterochromatin; histones; Histones - metabolism; lysine; Male; mechanical properties; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; methyltransferases; Migration; mitogen-activated protein kinase; Nuclear mechanics; Osteopontin; Osteopontin - metabolism; Rats; Rats, Sprague-Dawley; stem cells; Chromatin; Migration; H3K9me3; AFM; OPN; BSA; DMEM; LINC; shRNA; FBS; ERK 1/2; PBS; TSA; TBS; CSK buffer; Osteopontin; DAPI; HMT; MEK; Bone marrow-derived mesenchymal stem cells (BMSCs); PRC2; Nuclear mechanics; ERK1/2 signalling; BMSCs; EZH2; H3K27me3; HDAC
• ISSN: 1357-2725; 1878-5875; 1878-5875
• DOI: 10.1016/j.biocel.2018.01.006

In non-migrating BMSCs, chromatin is organized into highly condensed heterochromatin regions and non-condensed euchromatin regions. During BMSC migration through interstitial tissues, the deformability of the relatively rigid nucleus may constitute a rate-limiting step. OPN-mediated BMSC migration leads to elevated levels of the heterochromatin marker H3K27me3 through the methyltransferase EZH2. Increased heterochromatinization in the migrating cell may contribute to decreased nuclear size and better nuclear reshaping through the following mechanisms: (i) condensed chromatin can pull the nuclear envelope inward to support a reduction in nuclear size; (ii) condensed chromatin can form stronger anchoring points for the LINC complex, strengthening the interaction between the cytoskeleton and the nucleus, thus making it easier for the cytoskeleton to move the nucleus within the cell. [Display omitted] •OPN-induced BMSC migration increases chromatin compaction and the levels of heterochromatin-specific epigenetic markers.•OPN-induced BMSC migration increases the levels of EZH2 histone methyltransferase.•Pharmacological inhibition or depletion of EZH2 suppresses BMSC migration.•Chromatin structure may affect the mechanical properties of the nucleus and BMSC migration.•OPN increases BMSC chromatin condensation via the ERK1/2 signaling pathway. Osteopontin (OPN) is a chemokine-like extracellular matrix-associated protein involved in the migration of bone marrow-derived mesenchymal stem cells (BMSCs). An increasing number of studies have found that chromatin organization may affect cellular migration. However, whether OPN regulates chromatin organization is not understood, nor are the underlying molecular mechanisms. In this study, we investigated the link between chromatin organization and BMSC migration and demonstrated that OPN-mediated BMSC migration leads to elevated levels of heterochromatin marker histone H3 lysine 27 trimethylation (H3K27me3) through the methyltransferase EZH2. The expression of EZH2 reorganizes the chromatin structure of BMSCs. Pharmacological inhibition or depletion of EZH2 blocks BMSC migration. Moreover, using an atomic force microscope (AFM), we found that chromatin decondensation alters the mechanical properties of the nucleus. In addition, inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signals represses OPN-promoted chromatin condensation and cell migration. Thus, our results identify a mechanism by which ERK1/2 signalling drives specific chromatin modifications in BMSCs, which alters chromatin organization and thereby enables OPN-mediated BMSC migration.