DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease
Dendritic cells (DCs) are heterogeneous immune regulators involved in autoimmune diseases. Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome met...
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| Veröffentlicht in: | The Journal of immunology (1950) 2022-01, Vol.208 (2), p.358-370 |
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| creator | Czeh, Melinda Stäble, Sina Krämer, Stephen Tepe, Lena Talyan, Sweta Carrelha, Joana Meng, Yiran Heitplatz, Barbara Schwabenland, Marius Milsom, Michael D Plass, Christoph Prinz, Marco Schlesner, Matthias Andrade-Navarro, Miguel A Nerlov, Claus Jacobsen, Sten Eirik W Lipka, Daniel B Rosenbauer, Frank |
| description | Dendritic cells (DCs) are heterogeneous immune regulators involved in autoimmune diseases. Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome methylation assessment with the analysis of mice expressing reduced DNA methyltransferase 1 levels, we show that distinct DNA methylation levels and patterns are required for the development of plasmacytoid DC and conventional DC subsets. We provide clonal in vivo evidence for DC lineage establishment at the stem cell level, and we show that a high DNA methylation threshold level is essential for Flt3-dependent survival of DC precursors. Importantly, reducing methylation predominantly depletes plasmacytoid DC and alleviates systemic lupus erythematosus in an autoimmunity mouse model. This study shows how DNA methylation regulates the production of DC subsets and provides a potential rationale for targeting autoimmune disease using hypomethylating agents. |
| doi_str_mv | 10.4049/jimmunol.2100624 |
| format | Article |
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Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome methylation assessment with the analysis of mice expressing reduced DNA methyltransferase 1 levels, we show that distinct DNA methylation levels and patterns are required for the development of plasmacytoid DC and conventional DC subsets. We provide clonal in vivo evidence for DC lineage establishment at the stem cell level, and we show that a high DNA methylation threshold level is essential for Flt3-dependent survival of DC precursors. Importantly, reducing methylation predominantly depletes plasmacytoid DC and alleviates systemic lupus erythematosus in an autoimmunity mouse model. This study shows how DNA methylation regulates the production of DC subsets and provides a potential rationale for targeting autoimmune disease using hypomethylating agents.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.2100624</identifier><identifier>PMID: 34903641</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Autoimmunity - genetics ; Bone Marrow Cells - immunology ; Cell Differentiation - immunology ; Dendritic Cells - cytology ; Dendritic Cells - immunology ; DNA (Cytosine-5-)-Methyltransferase 1 - genetics ; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism ; DNA Methylation - genetics ; Gene Expression Profiling ; Hematopoietic Stem Cells - cytology ; Homeostasis - immunology ; Lupus Erythematosus, Systemic - immunology ; Mice ; Mice, Knockout</subject><ispartof>The Journal of immunology (1950), 2022-01, Vol.208 (2), p.358-370</ispartof><rights>Copyright © 2022 by The American Association of Immunologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c434t-ac0396492b74972191b708d5d896a75d02086f0510de8a674ec0eb9992ab942c3</citedby><cites>FETCH-LOGICAL-c434t-ac0396492b74972191b708d5d896a75d02086f0510de8a674ec0eb9992ab942c3</cites><orcidid>0000-0002-5896-4086 ; 0000-0001-6650-1711 ; 0000-0002-7160-6742 ; 0000-0001-7977-9421 ; 0000-0002-5962-2440 ; 0000-0003-2205-5427 ; 0000-0002-9333-2383 ; 0000-0001-5081-7869 ; 0000-0002-3567-254X ; 0000-0003-2554-3952</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,550,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34903641$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:148777792$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Czeh, Melinda</creatorcontrib><creatorcontrib>Stäble, Sina</creatorcontrib><creatorcontrib>Krämer, Stephen</creatorcontrib><creatorcontrib>Tepe, Lena</creatorcontrib><creatorcontrib>Talyan, Sweta</creatorcontrib><creatorcontrib>Carrelha, Joana</creatorcontrib><creatorcontrib>Meng, Yiran</creatorcontrib><creatorcontrib>Heitplatz, Barbara</creatorcontrib><creatorcontrib>Schwabenland, Marius</creatorcontrib><creatorcontrib>Milsom, Michael D</creatorcontrib><creatorcontrib>Plass, Christoph</creatorcontrib><creatorcontrib>Prinz, Marco</creatorcontrib><creatorcontrib>Schlesner, Matthias</creatorcontrib><creatorcontrib>Andrade-Navarro, Miguel A</creatorcontrib><creatorcontrib>Nerlov, Claus</creatorcontrib><creatorcontrib>Jacobsen, Sten Eirik W</creatorcontrib><creatorcontrib>Lipka, Daniel B</creatorcontrib><creatorcontrib>Rosenbauer, Frank</creatorcontrib><title>DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Dendritic cells (DCs) are heterogeneous immune regulators involved in autoimmune diseases. Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome methylation assessment with the analysis of mice expressing reduced DNA methyltransferase 1 levels, we show that distinct DNA methylation levels and patterns are required for the development of plasmacytoid DC and conventional DC subsets. We provide clonal in vivo evidence for DC lineage establishment at the stem cell level, and we show that a high DNA methylation threshold level is essential for Flt3-dependent survival of DC precursors. Importantly, reducing methylation predominantly depletes plasmacytoid DC and alleviates systemic lupus erythematosus in an autoimmunity mouse model. This study shows how DNA methylation regulates the production of DC subsets and provides a potential rationale for targeting autoimmune disease using hypomethylating agents.</description><subject>Animals</subject><subject>Autoimmunity - genetics</subject><subject>Bone Marrow Cells - immunology</subject><subject>Cell Differentiation - immunology</subject><subject>Dendritic Cells - cytology</subject><subject>Dendritic Cells - immunology</subject><subject>DNA (Cytosine-5-)-Methyltransferase 1 - genetics</subject><subject>DNA (Cytosine-5-)-Methyltransferase 1 - metabolism</subject><subject>DNA Methylation - genetics</subject><subject>Gene Expression Profiling</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Homeostasis - immunology</subject><subject>Lupus Erythematosus, Systemic - immunology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNpVkc1v1DAQxS0Eokvhzgn5yCVl7Dj2-oJU7RZaqXwcyhXLcWbBJbGXTEK1_z1e7bZqTx55fu_NaB5jbwWcKVD2w20chjnl_kwKAC3VM7YQTQOV1qCfswWAlJUw2pywV0S3UBiQ6iU7qZWFWiuxYD_XX7_cCL7GTQwRU9jxq2Hrw0Q8J_699zT4sJty7AqSujFOMfAV9j3xmPhlHjDT5CkS96nj53Mh9xshX0dCT_iavdj4nvDN8T1lPz5d3Kwuq-tvn69W59dVULWaKh-gtlpZ2RpljRRWtAaWXdMtrfam6UDCUm-gEdDh0mujMAC21lrpW6tkqE9ZdfClO9zOrduOcfDjzmUf3fHrT6nQqUbbui78xwNfOgN2AdM0-v6J7Gknxd_uV_7njBZSSigG748GY_47I01uiBTKYXzCPJOTuiRirNJ7FA5oGDPRiJuHMQLcPkZ3H6M7xlgk7x6v9yC4z63-D9KOm9w</recordid><startdate>20220115</startdate><enddate>20220115</enddate><creator>Czeh, Melinda</creator><creator>Stäble, Sina</creator><creator>Krämer, Stephen</creator><creator>Tepe, Lena</creator><creator>Talyan, Sweta</creator><creator>Carrelha, Joana</creator><creator>Meng, Yiran</creator><creator>Heitplatz, Barbara</creator><creator>Schwabenland, Marius</creator><creator>Milsom, Michael D</creator><creator>Plass, Christoph</creator><creator>Prinz, Marco</creator><creator>Schlesner, Matthias</creator><creator>Andrade-Navarro, Miguel A</creator><creator>Nerlov, Claus</creator><creator>Jacobsen, Sten Eirik W</creator><creator>Lipka, Daniel B</creator><creator>Rosenbauer, Frank</creator><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>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0002-5896-4086</orcidid><orcidid>https://orcid.org/0000-0001-6650-1711</orcidid><orcidid>https://orcid.org/0000-0002-7160-6742</orcidid><orcidid>https://orcid.org/0000-0001-7977-9421</orcidid><orcidid>https://orcid.org/0000-0002-5962-2440</orcidid><orcidid>https://orcid.org/0000-0003-2205-5427</orcidid><orcidid>https://orcid.org/0000-0002-9333-2383</orcidid><orcidid>https://orcid.org/0000-0001-5081-7869</orcidid><orcidid>https://orcid.org/0000-0002-3567-254X</orcidid><orcidid>https://orcid.org/0000-0003-2554-3952</orcidid></search><sort><creationdate>20220115</creationdate><title>DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease</title><author>Czeh, Melinda ; 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Epigenomic mechanisms orchestrating DC development and DC subset diversification remain insufficiently understood but could be important to modulate DC fate for clinical purposes. By combining whole-genome methylation assessment with the analysis of mice expressing reduced DNA methyltransferase 1 levels, we show that distinct DNA methylation levels and patterns are required for the development of plasmacytoid DC and conventional DC subsets. We provide clonal in vivo evidence for DC lineage establishment at the stem cell level, and we show that a high DNA methylation threshold level is essential for Flt3-dependent survival of DC precursors. Importantly, reducing methylation predominantly depletes plasmacytoid DC and alleviates systemic lupus erythematosus in an autoimmunity mouse model. 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| subjects | Animals Autoimmunity - genetics Bone Marrow Cells - immunology Cell Differentiation - immunology Dendritic Cells - cytology Dendritic Cells - immunology DNA (Cytosine-5-)-Methyltransferase 1 - genetics DNA (Cytosine-5-)-Methyltransferase 1 - metabolism DNA Methylation - genetics Gene Expression Profiling Hematopoietic Stem Cells - cytology Homeostasis - immunology Lupus Erythematosus, Systemic - immunology Mice Mice, Knockout |
| title | DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease |
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