{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:55:16Z","timestamp":1794048916303,"version":"4.8.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People's Republic of China","doi-asserted-by":"publisher","award":["2016YFC1302103, 2015CB553906"],"award-info":[{"award-number":["2016YFC1302103, 2015CB553906"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81472734, 81230051, 81500180 and 31170711"],"award-info":[{"award-number":["81472734, 81230051, 81500180 and 31170711"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81500180"],"award-info":[{"award-number":["81500180"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7120002 and 7171005"],"award-info":[{"award-number":["7120002 and 7171005"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Kindlin-2 plays an important role in the regulation of cardiac structure and function. Depletion of Kindlin-2 contributes to cardiac hypertrophy and progressive heart failure, however, the precise mechanisms involved in this process remain unclear<jats:italic>. GATA4<\/jats:italic> is a critical transcription factor in regulating cardiogenesis. We found that Kindlin-2 suppresses the expression of <jats:italic>GATA4<\/jats:italic> through binding to its promoter and prevents cardiomyocytes from hypertrophy induced by isoproterenol (ISO) treatment. Mechanistically, Kindlin-2 interacts with histone methyltransferase SUV39H1 and recruits it to <jats:italic>GATA4<\/jats:italic> promoter leading to the occupancy of histone H3K9 di- and tri-methylation. Furthermore, to confirm the function of Kindlin-2 in vivo, we generated mice with targeted deletion of cardiac Kindlin-2. We found that 6-month-old Kindlin-2 cKO mice have developed hypertrophic cardiomyopathy and that this pathological process can be accelerated by ISO-treatment. <jats:italic>GATA4<\/jats:italic> expression was markedly activated in cardiac tissues of Kindlin-2 cKO mice compared to wild-type animals. Collectively, our data revealed that Kindlin-2 suppresses <jats:italic>GATA4<\/jats:italic> expression by triggering histone H3K9 methylation in part and protects heart from pathological hypertrophy.<\/jats:p>","DOI":"10.1038\/s41419-019-2121-0","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:04:33Z","timestamp":1574726673000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Kindlin-2 suppresses transcription factor GATA4 through interaction with SUV39H1 to attenuate hypertrophy"],"prefix":"10.1038","volume":"10","author":[{"given":"Lihua","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqian","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengchang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junzhou","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongquan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"2121_CR1","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1038\/nrcardio.2010.137","volume":"7","author":"N Ajmone Marsan","year":"2010","unstructured":"Ajmone Marsan, N. & Bax, J. J. Cardiomyopathies: Myocardial fibrosis assessed by CMR to predict events in HCM. Nat. Rev. Cardiol. 7, 604\u2013606 (2010).","journal-title":"Nat. Rev. Cardiol."},{"key":"2121_CR2","doi-asserted-by":"publisher","first-page":"2214","DOI":"10.1128\/MCB.00218-12","volume":"32","author":"JM Gallagher","year":"2012","unstructured":"Gallagher, J. M., Komati, H., Roy, E., Nemer, M. & Latinkic, B. V. Dissociation of cardiogenic and postnatal myocardial activities of GATA4. Mol. Cell. Biol. 32, 2214\u20132223 (2012).","journal-title":"Mol. Cell. Biol."},{"key":"2121_CR3","doi-asserted-by":"publisher","first-page":"9828","DOI":"10.1074\/jbc.M707391200","volume":"283","author":"T Takaya","year":"2008","unstructured":"Takaya, T. et al. Identification of p300-targeted acetylated residues in GATA4 during hypertrophic responses in cardiac myocytes. J. Biol. Chem. 283, 9828\u20139835 (2008).","journal-title":"J. Biol. Chem."},{"issue":"6","key":"2121_CR4","doi-asserted-by":"publisher","first-page":"9047","DOI":"10.1002\/jcb.28178","volume":"120","author":"Yao Xu","year":"2018","unstructured":"Xu, Y., Liang, C., Luo, Y., Xing, W. & Zhang, T. Possible mechanism of GATA4 inhibiting myocardin activity during cardiac hypertrophy. J. Cell. Biochem., https:\/\/doi.org\/10.1002\/jcb.28178 (2018).","journal-title":"Journal of Cellular Biochemistry"},{"key":"2121_CR5","doi-asserted-by":"publisher","first-page":"30245","DOI":"10.1074\/jbc.M102174200","volume":"276","author":"Q Liang","year":"2001","unstructured":"Liang, Q. et al. The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J. Biol. Chem. 276, 30245\u201330253 (2001).","journal-title":"J. Biol. Chem."},{"key":"2121_CR6","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.gene.2017.10.078","volume":"641","author":"Y Yu","year":"2018","unstructured":"Yu, Y. et al. Functional mutant GATA4 identification and potential application in preimplantation diagnosis of congenital heart diseases. Gene 641, 349\u2013354 (2018).","journal-title":"Gene"},{"key":"2121_CR7","doi-asserted-by":"publisher","first-page":"12573","DOI":"10.1073\/pnas.0400752101","volume":"101","author":"AJ Watt","year":"2004","unstructured":"Watt, A. J., Battle, M. A., Li, J. & Duncan, S. A. GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc. Natl Acad. Sci. USA 101, 12573\u201312578 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2121_CR8","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/S0092-8674(02)00971-6","volume":"110","author":"RO Hynes","year":"2002","unstructured":"Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673\u2013687 (2002).","journal-title":"Cell"},{"key":"2121_CR9","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1002\/path.1472","volume":"201","author":"EH Danen","year":"2003","unstructured":"Danen, E. H. & Sonnenberg, A. Integrins in regulation of tissue development and function. J. Pathol. 201, 632\u2013641 (2003).","journal-title":"J. Pathol."},{"key":"2121_CR10","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1161\/hh0402.105790","volume":"90","author":"SY Shai","year":"2002","unstructured":"Shai, S. Y. et al. Cardiac myocyte-specific excision of the beta1 integrin gene results in myocardial fibrosis and cardiac failure. Circulation Res. 90, 458\u2013464 (2002).","journal-title":"Circulation Res."},{"key":"2121_CR11","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.1101\/gad.1458906","volume":"20","author":"DE White","year":"2006","unstructured":"White, D. E. et al. Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure. Genes Dev. 20, 2355\u20132360 (2006).","journal-title":"Genes Dev."},{"key":"2121_CR12","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/0092-8674(95)90184-1","volume":"83","author":"C Wu","year":"1995","unstructured":"Wu, C., Keivens, V. M., O\u2019Toole, T. E., McDonald, J. A. & Ginsberg, M. H. Integrin activation and cytoskeletal interaction are essential for the assembly of a fibronectin matrix. Cell 83, 715\u2013724 (1995).","journal-title":"Cell"},{"key":"2121_CR13","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1161\/CIRCRESAHA.107.161489","volume":"102","author":"JJ Dowling","year":"2008","unstructured":"Dowling, J. J. et al. Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circulation Res. 102, 423\u2013431 (2008).","journal-title":"Circulation Res."},{"key":"2121_CR14","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1016\/j.febslet.2015.06.022","volume":"589","author":"L Qi","year":"2015","unstructured":"Qi, L. et al. Kindlin-2 interacts with alpha-actinin-2 and beta1 integrin to maintain the integrity of the Z-disc in cardiac muscles. FEBS Lett. 589, 2155\u20132162 (2015).","journal-title":"FEBS Lett."},{"key":"2121_CR15","doi-asserted-by":"publisher","unstructured":"Zhang, Z. et al. Postnatal loss of Kindlin-2 leads to progressive heart failure. Circ. Heart Fail. 9, https:\/\/doi.org\/10.1161\/CIRCHEARTFAILURE.116.003129 (2016).","DOI":"10.1161\/CIRCHEARTFAILURE.116.003129"},{"key":"2121_CR16","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1002\/ijc.28151","volume":"133","author":"Y Yu","year":"2013","unstructured":"Yu, Y. et al. Kindlin 2 promotes breast cancer invasion via epigenetic silencing of the microRNA200 gene family. Int. J. Cancer 133, 1368\u20131379 (2013).","journal-title":"Int. J. Cancer"},{"key":"2121_CR17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.biocel.2018.09.022","volume":"105","author":"P Wang","year":"2018","unstructured":"Wang, P. et al. Kindlin-2 interacts with and stabilizes DNMT1 to promote breast cancer development. Int. J. Biochem. cell Biol. 105, 41\u201351 (2018).","journal-title":"Int. J. Biochem. cell Biol."},{"key":"2121_CR18","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1038\/embor.2012.88","volume":"13","author":"Y Yu","year":"2012","unstructured":"Yu, Y. et al. Kindlin 2 forms a transcriptional complex with beta-catenin and TCF4 to enhance Wnt signalling. EMBO Rep. 13, 750\u2013758 (2012).","journal-title":"EMBO Rep."},{"key":"2121_CR19","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.yjmcc.2015.09.010","volume":"88","author":"G Mehta","year":"2015","unstructured":"Mehta, G. et al. MITF interacts with the SWI\/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy. J. Mol. Cell Cardiol. 88, 101\u2013110 (2015).","journal-title":"J. Mol. Cell Cardiol."},{"key":"2121_CR20","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-013-0374-9","volume":"108","author":"Y Huang","year":"2013","unstructured":"Huang, Y. et al. Deficiency of cartilage oligomeric matrix protein causes dilated cardiomyopathy. Basic Res. Cardiol. 108, 374 (2013).","journal-title":"Basic Res. Cardiol."},{"key":"2121_CR21","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1016\/S1097-2765(03)00479-9","volume":"12","author":"JC Rice","year":"2003","unstructured":"Rice, J. C. et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell 12, 1591\u20131598 (2003).","journal-title":"Mol. Cell"},{"key":"2121_CR22","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S1097-2765(03)00477-5","volume":"12","author":"AH Peters","year":"2003","unstructured":"Peters, A. H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577\u20131589 (2003).","journal-title":"Mol. Cell"},{"key":"2121_CR23","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1161\/01.RES.0000215985.18538.c4","volume":"98","author":"T Oka","year":"2006","unstructured":"Oka, T. et al. Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circulation Res. 98, 837\u2013845 (2006).","journal-title":"Circulation Res."},{"key":"2121_CR24","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1111\/cpr.12253","volume":"49","author":"H Xu","year":"2016","unstructured":"Xu, H. et al. Histone modifications interact with DNA methylation at the GATA4 promoter during differentiation of mesenchymal stem cells into cardiomyocyte-like cells. Cell Prolif. 49, 315\u2013329 (2016).","journal-title":"Cell Prolif."},{"key":"2121_CR25","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.cardiores.2004.03.025","volume":"63","author":"S Pikkarainen","year":"2004","unstructured":"Pikkarainen, S., Tokola, H., Kerkela, R. & Ruskoaho, H. GATA transcription factors in the developing and adult heart. Cardiovascular Res. 63, 196\u2013207 (2004).","journal-title":"Cardiovascular Res."},{"key":"2121_CR26","doi-asserted-by":"publisher","unstructured":"Lai, H. T., Tseng, W. K., Huang, S. W., Chao, T. C. & Su, Y. MicroRNA-203 diminishes the stemness of human colon cancer cells by suppressing GATA6 expression. J. Cell. Physiol. https:\/\/doi.org\/10.1002\/jcp.29192 (2019).","DOI":"10.1002\/jcp.29192"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2121-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2121-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2121-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T18:00:31Z","timestamp":1671213631000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-019-2121-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,26]]},"references-count":26,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["2121"],"URL":"https:\/\/doi.org\/10.1038\/s41419-019-2121-0","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,26]]},"assertion":[{"value":"15 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 November 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2019","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"890"}}