MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening
Somatic cell reprogramming is an ideal model for studying epigenetic regulation as it undergoes dramatic chromatin remodeling. However, a role for phosphorylation signaling in chromatin protein modifications for reprogramming remains unclear. Here, we identified mitogen-activated protein kinase kina...
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| Veröffentlicht in: | Cell death and differentiation 2022-05, Vol.29 (5), p.1042-1054 |
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| creator | Xing, Guangsuo Liu, Zichao Huang, Luyuan Zhao, Danyun Wang, Tao Yuan, Hao Wu, Yi Li, Linpeng Long, Qi Zhou, Yanshuang Hao, Zhihong Liu, Yang Lu, Jianghuan Li, Shiting Zhu, Jieying Wang, Bo Wang, Junwei Liu, Jing Chen, Jiekai Pei, Duanqing Liu, Xingguo Chen, Keshi |
| description | Somatic cell reprogramming is an ideal model for studying epigenetic regulation as it undergoes dramatic chromatin remodeling. However, a role for phosphorylation signaling in chromatin protein modifications for reprogramming remains unclear. Here, we identified mitogen-activated protein kinase kinase 6 (Mkk6) as a chromatin relaxer and found that it could significantly enhance reprogramming. The function of Mkk6 in heterochromatin loosening and reprogramming requires its kinase activity but does not depend on its best-known target, P38. We identified Gatad2b as a novel target of Mkk6 phosphorylation that acts downstream to elevate histone acetylation levels and loosen heterochromatin. As a result, Mkk6 over-expression facilitates binding of Sox2 and Klf4 to their targets and promotes pluripotency gene expression during reprogramming. Our studies not only reveal an Mkk phosphorylation mediated modulation of chromatin status in reprogramming, but also provide new rationales to further investigate and improve the cell fate determination processes. |
| doi_str_mv | 10.1038/s41418-021-00902-z |
| format | Article |
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However, a role for phosphorylation signaling in chromatin protein modifications for reprogramming remains unclear. Here, we identified mitogen-activated protein kinase kinase 6 (Mkk6) as a chromatin relaxer and found that it could significantly enhance reprogramming. The function of Mkk6 in heterochromatin loosening and reprogramming requires its kinase activity but does not depend on its best-known target, P38. We identified Gatad2b as a novel target of Mkk6 phosphorylation that acts downstream to elevate histone acetylation levels and loosen heterochromatin. As a result, Mkk6 over-expression facilitates binding of Sox2 and Klf4 to their targets and promotes pluripotency gene expression during reprogramming. Our studies not only reveal an Mkk phosphorylation mediated modulation of chromatin status in reprogramming, but also provide new rationales to further investigate and improve the cell fate determination processes.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-021-00902-z</identifier><identifier>PMID: 34815549</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/100 ; 14/19 ; 631/208/176 ; 631/337/100/102 ; Acetylation ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Cycle Analysis ; Cell fate ; Cellular Reprogramming ; Chromatin ; Chromatin remodeling ; Epigenesis, Genetic ; Epigenetics ; Gene expression ; Heterochromatin ; Histones ; Kinases ; KLF4 protein ; Life Sciences ; MAP kinase ; MAP Kinase Kinase 6 - genetics ; MAP Kinase Kinase 6 - metabolism ; MKK6 protein ; Overexpression ; Phosphorylation ; Pluripotency ; Protein kinase ; Stem Cells</subject><ispartof>Cell death and differentiation, 2022-05, Vol.29 (5), p.1042-1054</ispartof><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2021. corrected publication 2021</rights><rights>2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.</rights><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2021. corrected publication 2021.</rights><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2021, corrected publication 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-6ac31eddbe1d3f1f678aa646bbd536dd38597dc893232a090d833fa93576f38b3</citedby><cites>FETCH-LOGICAL-c474t-6ac31eddbe1d3f1f678aa646bbd536dd38597dc893232a090d833fa93576f38b3</cites><orcidid>0000-0003-0494-4749 ; 0000-0002-2951-9215 ; 0000-0003-0106-4658 ; 0000-0002-5222-014X ; 0000-0001-7247-7404 ; 0000-0001-7060-8204 ; 0000-0003-0402-4555 ; 0000-0002-7003-0104</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090911/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090911/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34815549$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xing, Guangsuo</creatorcontrib><creatorcontrib>Liu, Zichao</creatorcontrib><creatorcontrib>Huang, Luyuan</creatorcontrib><creatorcontrib>Zhao, Danyun</creatorcontrib><creatorcontrib>Wang, Tao</creatorcontrib><creatorcontrib>Yuan, Hao</creatorcontrib><creatorcontrib>Wu, Yi</creatorcontrib><creatorcontrib>Li, Linpeng</creatorcontrib><creatorcontrib>Long, Qi</creatorcontrib><creatorcontrib>Zhou, Yanshuang</creatorcontrib><creatorcontrib>Hao, Zhihong</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Lu, Jianghuan</creatorcontrib><creatorcontrib>Li, Shiting</creatorcontrib><creatorcontrib>Zhu, Jieying</creatorcontrib><creatorcontrib>Wang, Bo</creatorcontrib><creatorcontrib>Wang, Junwei</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Chen, Jiekai</creatorcontrib><creatorcontrib>Pei, Duanqing</creatorcontrib><creatorcontrib>Liu, Xingguo</creatorcontrib><creatorcontrib>Chen, Keshi</creatorcontrib><title>MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>Somatic cell reprogramming is an ideal model for studying epigenetic regulation as it undergoes dramatic chromatin remodeling. However, a role for phosphorylation signaling in chromatin protein modifications for reprogramming remains unclear. Here, we identified mitogen-activated protein kinase kinase 6 (Mkk6) as a chromatin relaxer and found that it could significantly enhance reprogramming. The function of Mkk6 in heterochromatin loosening and reprogramming requires its kinase activity but does not depend on its best-known target, P38. We identified Gatad2b as a novel target of Mkk6 phosphorylation that acts downstream to elevate histone acetylation levels and loosen heterochromatin. As a result, Mkk6 over-expression facilitates binding of Sox2 and Klf4 to their targets and promotes pluripotency gene expression during reprogramming. Our studies not only reveal an Mkk phosphorylation mediated modulation of chromatin status in reprogramming, but also provide new rationales to further investigate and improve the cell fate determination processes.</description><subject>13/1</subject><subject>13/100</subject><subject>14/19</subject><subject>631/208/176</subject><subject>631/337/100/102</subject><subject>Acetylation</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell fate</subject><subject>Cellular Reprogramming</subject><subject>Chromatin</subject><subject>Chromatin remodeling</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Heterochromatin</subject><subject>Histones</subject><subject>Kinases</subject><subject>KLF4 protein</subject><subject>Life Sciences</subject><subject>MAP kinase</subject><subject>MAP Kinase Kinase 6 - genetics</subject><subject>MAP Kinase Kinase 6 - metabolism</subject><subject>MKK6 protein</subject><subject>Overexpression</subject><subject>Phosphorylation</subject><subject>Pluripotency</subject><subject>Protein kinase</subject><subject>Stem Cells</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU1vFSEUhonR2A_9Ay4MiRs3KF_DDBuTptFqrNGFrgkDZ-ZOMwMjcJvc7vznpb21VRcuCITzvC_n8CL0gtE3jIrubZZMso5QzgilmnJy9QgdMtkq0kgqHtezaCjRVLYH6CjnC0qparV6ig6E7FjTSH2Ifn05-cY_K5xgiR7mjN0mxcWWKWAbPB6sm-ap2AK5ImuKY7LLMoUR9ztsXZkub9ARn9liPe_Juom5rrSb630M2MMKwUMoeAMFUnxwn2PMEKr2GXoy2DnD87v9GP348P776Udy_vXs0-nJOXGylYUo6wQD73tgXgxsUG1nrZKq730jlPeia3TrXacFF9zW7_CdEIPVomnVILpeHKN3e9912y_gXW0q2dmsaVps2ploJ_N3JUwbM8ZLo6uZZqwavL4zSPHnFnIxy5QdzLMNELfZcEWZ1pLdoq_-QS_iNoU6XqUUazlnmleK7ymXYs4JhvtmGDU3CZt9wqYmbG4TNldV9PLPMe4lvyOtgNgDuZbCCOnh7f_YXgMqgbXm</recordid><startdate>20220501</startdate><enddate>20220501</enddate><creator>Xing, Guangsuo</creator><creator>Liu, Zichao</creator><creator>Huang, Luyuan</creator><creator>Zhao, Danyun</creator><creator>Wang, Tao</creator><creator>Yuan, Hao</creator><creator>Wu, Yi</creator><creator>Li, Linpeng</creator><creator>Long, Qi</creator><creator>Zhou, Yanshuang</creator><creator>Hao, Zhihong</creator><creator>Liu, Yang</creator><creator>Lu, Jianghuan</creator><creator>Li, Shiting</creator><creator>Zhu, Jieying</creator><creator>Wang, Bo</creator><creator>Wang, Junwei</creator><creator>Liu, Jing</creator><creator>Chen, Jiekai</creator><creator>Pei, Duanqing</creator><creator>Liu, Xingguo</creator><creator>Chen, Keshi</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0494-4749</orcidid><orcidid>https://orcid.org/0000-0002-2951-9215</orcidid><orcidid>https://orcid.org/0000-0003-0106-4658</orcidid><orcidid>https://orcid.org/0000-0002-5222-014X</orcidid><orcidid>https://orcid.org/0000-0001-7247-7404</orcidid><orcidid>https://orcid.org/0000-0001-7060-8204</orcidid><orcidid>https://orcid.org/0000-0003-0402-4555</orcidid><orcidid>https://orcid.org/0000-0002-7003-0104</orcidid></search><sort><creationdate>20220501</creationdate><title>MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening</title><author>Xing, Guangsuo ; Liu, Zichao ; Huang, Luyuan ; Zhao, Danyun ; Wang, Tao ; Yuan, Hao ; Wu, Yi ; Li, Linpeng ; Long, Qi ; Zhou, Yanshuang ; Hao, Zhihong ; Liu, Yang ; Lu, Jianghuan ; Li, Shiting ; Zhu, Jieying ; Wang, Bo ; Wang, Junwei ; Liu, Jing ; Chen, Jiekai ; Pei, Duanqing ; Liu, Xingguo ; Chen, Keshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-6ac31eddbe1d3f1f678aa646bbd536dd38597dc893232a090d833fa93576f38b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>13/1</topic><topic>13/100</topic><topic>14/19</topic><topic>631/208/176</topic><topic>631/337/100/102</topic><topic>Acetylation</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell fate</topic><topic>Cellular Reprogramming</topic><topic>Chromatin</topic><topic>Chromatin remodeling</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Heterochromatin</topic><topic>Histones</topic><topic>Kinases</topic><topic>KLF4 protein</topic><topic>Life Sciences</topic><topic>MAP kinase</topic><topic>MAP Kinase Kinase 6 - 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| ispartof | Cell death and differentiation, 2022-05, Vol.29 (5), p.1042-1054 |
| issn | 1350-9047 1476-5403 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 13/1 13/100 14/19 631/208/176 631/337/100/102 Acetylation Apoptosis Biochemistry Biomedical and Life Sciences Cell Biology Cell Cycle Analysis Cell fate Cellular Reprogramming Chromatin Chromatin remodeling Epigenesis, Genetic Epigenetics Gene expression Heterochromatin Histones Kinases KLF4 protein Life Sciences MAP kinase MAP Kinase Kinase 6 - genetics MAP Kinase Kinase 6 - metabolism MKK6 protein Overexpression Phosphorylation Pluripotency Protein kinase Stem Cells |
| title | MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening |
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