KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis
Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1 + CD11b + MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expressio...
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| Veröffentlicht in: | Journal of Innate Immunity 2022, Vol.14 (2), p.112-123 |
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| container_title | Journal of Innate Immunity |
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| creator | Bah, Isatou Alkhateeb, Tuqa Youssef, Dima Yao, Zhi Q. McCall, Charles E. El Gazzar, Mohamed |
| description | Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1 + CD11b + MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site. |
| doi_str_mv | 10.1159/000517407 |
| format | Article |
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We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1 + CD11b + MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.</description><identifier>ISSN: 1662-811X</identifier><identifier>EISSN: 1662-8128</identifier><identifier>DOI: 10.1159/000517407</identifier><identifier>PMID: 34289476</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Animals ; Epigenesis, Genetic ; Epigenetic inheritance ; epigenetics ; Ethylenediaminetetraacetic acid ; Health aspects ; Histone Demethylases - genetics ; Histone Demethylases - metabolism ; hotairm1 ; Imipenem ; immune suppression ; Infection ; Lysine ; Lysine - genetics ; Lysine - metabolism ; Mice ; MicroRNAs - genetics ; myeloid-derived suppressor cell ; Myeloid-Derived Suppressor Cells ; Research Article ; RNA ; sepsis ; Sepsis - genetics ; Sepsis - metabolism</subject><ispartof>Journal of Innate Immunity, 2022, Vol.14 (2), p.112-123</ispartof><rights>2021 The Author(s) Published by S. Karger AG, Basel</rights><rights>2021 The Author(s) Published by S. Karger AG, Basel.</rights><rights>COPYRIGHT 2022 S. Karger AG</rights><rights>Copyright © 2021 by S. Karger AG, Basel 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-c169deb83cc561e357112cfd2fbf96839d03cf385ed3a292a666c5c211cbaed93</citedby><cites>FETCH-LOGICAL-c529t-c169deb83cc561e357112cfd2fbf96839d03cf385ed3a292a666c5c211cbaed93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082193/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082193/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,4010,27612,27900,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34289476$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bah, Isatou</creatorcontrib><creatorcontrib>Alkhateeb, Tuqa</creatorcontrib><creatorcontrib>Youssef, Dima</creatorcontrib><creatorcontrib>Yao, Zhi Q.</creatorcontrib><creatorcontrib>McCall, Charles E.</creatorcontrib><creatorcontrib>El Gazzar, Mohamed</creatorcontrib><title>KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis</title><title>Journal of Innate Immunity</title><addtitle>J Innate Immun</addtitle><description>Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1 + CD11b + MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.</description><subject>Animals</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>epigenetics</subject><subject>Ethylenediaminetetraacetic acid</subject><subject>Health aspects</subject><subject>Histone Demethylases - genetics</subject><subject>Histone Demethylases - metabolism</subject><subject>hotairm1</subject><subject>Imipenem</subject><subject>immune suppression</subject><subject>Infection</subject><subject>Lysine</subject><subject>Lysine - genetics</subject><subject>Lysine - metabolism</subject><subject>Mice</subject><subject>MicroRNAs - genetics</subject><subject>myeloid-derived suppressor cell</subject><subject>Myeloid-Derived Suppressor Cells</subject><subject>Research Article</subject><subject>RNA</subject><subject>sepsis</subject><subject>Sepsis - genetics</subject><subject>Sepsis - metabolism</subject><issn>1662-811X</issn><issn>1662-8128</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>M--</sourceid><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNpVkk1v1DAQhiMEoqVw4I5QjnDY4u_EF6TVbluq7gpEQeJmee1x6pLEWzuLtP--brNErXyY0fidZ17LUxTvMTrFmMsvCCGOK4aqF8UxFoLMakzql1OO_xwVb1K6RUgwJqvXxRFlpJasEsfFz6vlWszL1T75HsoldDDc7Fudcu4jmCGVZ1vfQA-DN-WP0Oroh30ZXLleXi9SaXfR9025fghQXsM2-fS2eOV0m-DdIZ4Uv8_Pfi2-zVbfLy4X89XMcCKHmcFCWtjU1BguMFBeYUyMs8RtnBQ1lRZR42jNwVJNJNFCCMMNwdhsNFhJT4rLkWuDvlXb6Dsd9yporx4LITZKx2y7BQWIO46sBcc009ZqDdmEwIKRPMzhzPo6sra7TQfWQD9E3T6DPr_p_Y1qwj8lUU2wpBnw6QCI4W4HaVCdTwbaVvcQdkkRzhnljDCSpaejtNHZmu9dyESTj4XOm9CD87k-rzBHrKponRs-jw0mhpQiuMkXRuphAdS0AFn78elDJuX_H8-CD6Pgr44NxElw6L8HOhG0gg</recordid><startdate>2022</startdate><enddate>2022</enddate><creator>Bah, Isatou</creator><creator>Alkhateeb, Tuqa</creator><creator>Youssef, Dima</creator><creator>Yao, Zhi Q.</creator><creator>McCall, Charles E.</creator><creator>El Gazzar, Mohamed</creator><general>S. Karger AG</general><general>Karger Publishers</general><scope>M--</scope><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>IAO</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>2022</creationdate><title>KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis</title><author>Bah, Isatou ; Alkhateeb, Tuqa ; Youssef, Dima ; Yao, Zhi Q. ; McCall, Charles E. ; El Gazzar, Mohamed</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-c169deb83cc561e357112cfd2fbf96839d03cf385ed3a292a666c5c211cbaed93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>epigenetics</topic><topic>Ethylenediaminetetraacetic acid</topic><topic>Health aspects</topic><topic>Histone Demethylases - genetics</topic><topic>Histone Demethylases - metabolism</topic><topic>hotairm1</topic><topic>Imipenem</topic><topic>immune suppression</topic><topic>Infection</topic><topic>Lysine</topic><topic>Lysine - genetics</topic><topic>Lysine - metabolism</topic><topic>Mice</topic><topic>MicroRNAs - genetics</topic><topic>myeloid-derived suppressor cell</topic><topic>Myeloid-Derived Suppressor Cells</topic><topic>Research Article</topic><topic>RNA</topic><topic>sepsis</topic><topic>Sepsis - genetics</topic><topic>Sepsis - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bah, Isatou</creatorcontrib><creatorcontrib>Alkhateeb, Tuqa</creatorcontrib><creatorcontrib>Youssef, Dima</creatorcontrib><creatorcontrib>Yao, Zhi Q.</creatorcontrib><creatorcontrib>McCall, Charles E.</creatorcontrib><creatorcontrib>El Gazzar, Mohamed</creatorcontrib><collection>Karger Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale Academic OneFile</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal of Innate Immunity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bah, Isatou</au><au>Alkhateeb, Tuqa</au><au>Youssef, Dima</au><au>Yao, Zhi Q.</au><au>McCall, Charles E.</au><au>El Gazzar, Mohamed</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis</atitle><jtitle>Journal of Innate Immunity</jtitle><addtitle>J Innate Immun</addtitle><date>2022</date><risdate>2022</risdate><volume>14</volume><issue>2</issue><spage>112</spage><epage>123</epage><pages>112-123</pages><issn>1662-811X</issn><eissn>1662-8128</eissn><abstract>Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1 + CD11b + MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.</abstract><cop>Basel, Switzerland</cop><pub>S. 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| subjects | Animals Epigenesis, Genetic Epigenetic inheritance epigenetics Ethylenediaminetetraacetic acid Health aspects Histone Demethylases - genetics Histone Demethylases - metabolism hotairm1 Imipenem immune suppression Infection Lysine Lysine - genetics Lysine - metabolism Mice MicroRNAs - genetics myeloid-derived suppressor cell Myeloid-Derived Suppressor Cells Research Article RNA sepsis Sepsis - genetics Sepsis - metabolism |
| title | KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis |
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