Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation
A report of RNA 5-methylcytosine oxidation by mammalian Tet2, showing that Tet2 promotes infection-induced myelopoiesis in mice via a mechanism involving the repression of Socs3 mRNA, a previously unknown regulatory role of Tet2 at the epitranscriptomic level. mRNA oxidation mediates response to inf...
Gespeichert in:
| Veröffentlicht in: | Nature (London) 2018-02, Vol.554 (7690), p.123-127 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 127 |
|---|---|
| container_issue | 7690 |
| container_start_page | 123 |
| container_title | Nature (London) |
| container_volume | 554 |
| creator | Shen, Qicong Zhang, Qian Shi, Yang Shi, Qingzhu Jiang, Yanyan Gu, Yan Li, Zhiqing Li, Xia Zhao, Kai Wang, Chunmei Li, Nan Cao, Xuetao |
| description | A report of RNA 5-methylcytosine oxidation by mammalian Tet2, showing that Tet2 promotes infection-induced myelopoiesis in mice via a mechanism involving the repression of Socs3 mRNA, a previously unknown regulatory role of Tet2 at the epitranscriptomic level.
mRNA oxidation mediates response to infection
Messenger RNA (mRNA) can be modified biochemically without changing its ribonucleotide sequence. These mRNA modifications are essential for post-transcriptional regulation of gene expression. Xuetao Cao and colleagues report the oxidation of the RNA base 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) by the mammalian Tet2 enzyme. The authors also show that Tet2 promotes infection-induced myelopoiesis—generation of innate immune cells from the bone marrow—in mice. This effect occurs through a mechanism involving the destabilization of Socs3 mRNA caused by decreased levels of 5-mC. These findings highlight the role of epitranscriptome modifications in mammalian physiology.
Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation
1
. 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions
2
. The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins in
Drosophila
has been revealed more recently
3
,
4
. However, the turnover and function of 5-mC in mammalian mRNA have been largely unknown. Tet2 suppresses myeloid malignancies mostly in an enzymatic activity-dependent manner
5
, and is important in resolving inflammatory response in an enzymatic activity-independent way
6
. Myelopoiesis is a common host immune response in acute and chronic infections; however, its epigenetic mechanism needs to be identified. Here we demonstrate that Tet2 promotes infection-induced myelopoiesis in an mRNA oxidation-dependent manner through Adar1-mediated repression of Socs3 expression at the post-transcription level. Tet2 promotes both abdominal sepsis-induced emergency myelopoiesis and parasite-induced mast cell expansion through decreasing mRNA levels of Socs3, a key negative regulator of the JAK–STAT pathway that is critical for cytokine-induced myelopoiesis. Tet2 represses Socs3 expression through Adar1, which binds and destabilizes Socs3 mRNA in a RNA editing-independent manner. For the underlying mechanism of Tet2 regulation at the mRNA level, Tet2 mediates oxidation of 5-mC in mRNA. Tet2 deficiency leads to the transcriptome-w |
| doi_str_mv | 10.1038/nature25434 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_1991179793</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A525862847</galeid><sourcerecordid>A525862847</sourcerecordid><originalsourceid>FETCH-LOGICAL-c586t-28a083680fde4735ae4673a1feb9351e60ab3fc7926ef0972b1a788fa7f1c3813</originalsourceid><addsrcrecordid>eNpt0s-L1DAUB_AgijuOnrxLcS-Kds2PtkmPw-KPhUFhXc8hk750srRNN0lh9783ZVadkZJDIPnk8c3jIfSa4AuCmfg0qDh5oGXBiidoRQpe5UUl-FO0wpiKHAtWnaEXIdxijEvCi-fojNasKgTnK7S9gUiz0bveRQjZqOLetTBkdjCgo3VDbodm0tBk_QN0bnQWgg1Z3Hs3tfusv_6-ydy9bdRsX6JnRnUBXj3ua_Try-eby2_59sfXq8vNNtelqGJOhZpDCWwaKDgrFRQVZ4oY2NWsJFBhtWNG85pWYHDN6Y4oLoRR3BDNBGFr9O5QN-W-myBE2dugoevUAG4KktQ1IbzmNUv0_D966yY_pHSzKmhV4Fr8U63qQKa_u-iVnovKTUlTaCpS0DXKF1TqFnjVuQGMTccn_u2C16O9k8foYgGl1UBv9WLV9ycPkolwH1s1hSCvfl6f2g8Hq70LwYORo7e98g-SYDkPjzwanqTfPPZq2vXQ_LV_piWBjwcQ0tXQgj9q5kK938mny0o</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1994264098</pqid></control><display><type>article</type><title>Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation</title><source>MEDLINE</source><source>Nature</source><source>Alma/SFX Local Collection</source><creator>Shen, Qicong ; Zhang, Qian ; Shi, Yang ; Shi, Qingzhu ; Jiang, Yanyan ; Gu, Yan ; Li, Zhiqing ; Li, Xia ; Zhao, Kai ; Wang, Chunmei ; Li, Nan ; Cao, Xuetao</creator><creatorcontrib>Shen, Qicong ; Zhang, Qian ; Shi, Yang ; Shi, Qingzhu ; Jiang, Yanyan ; Gu, Yan ; Li, Zhiqing ; Li, Xia ; Zhao, Kai ; Wang, Chunmei ; Li, Nan ; Cao, Xuetao</creatorcontrib><description>A report of RNA 5-methylcytosine oxidation by mammalian Tet2, showing that Tet2 promotes infection-induced myelopoiesis in mice via a mechanism involving the repression of Socs3 mRNA, a previously unknown regulatory role of Tet2 at the epitranscriptomic level.
mRNA oxidation mediates response to infection
Messenger RNA (mRNA) can be modified biochemically without changing its ribonucleotide sequence. These mRNA modifications are essential for post-transcriptional regulation of gene expression. Xuetao Cao and colleagues report the oxidation of the RNA base 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) by the mammalian Tet2 enzyme. The authors also show that Tet2 promotes infection-induced myelopoiesis—generation of innate immune cells from the bone marrow—in mice. This effect occurs through a mechanism involving the destabilization of Socs3 mRNA caused by decreased levels of 5-mC. These findings highlight the role of epitranscriptome modifications in mammalian physiology.
Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation
1
. 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions
2
. The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins in
Drosophila
has been revealed more recently
3
,
4
. However, the turnover and function of 5-mC in mammalian mRNA have been largely unknown. Tet2 suppresses myeloid malignancies mostly in an enzymatic activity-dependent manner
5
, and is important in resolving inflammatory response in an enzymatic activity-independent way
6
. Myelopoiesis is a common host immune response in acute and chronic infections; however, its epigenetic mechanism needs to be identified. Here we demonstrate that Tet2 promotes infection-induced myelopoiesis in an mRNA oxidation-dependent manner through Adar1-mediated repression of Socs3 expression at the post-transcription level. Tet2 promotes both abdominal sepsis-induced emergency myelopoiesis and parasite-induced mast cell expansion through decreasing mRNA levels of Socs3, a key negative regulator of the JAK–STAT pathway that is critical for cytokine-induced myelopoiesis. Tet2 represses Socs3 expression through Adar1, which binds and destabilizes Socs3 mRNA in a RNA editing-independent manner. For the underlying mechanism of Tet2 regulation at the mRNA level, Tet2 mediates oxidation of 5-mC in mRNA. Tet2 deficiency leads to the transcriptome-wide appearance of methylated cytosines, including ones in the 3′ untranslated region of Socs3, which influences double-stranded RNA formation for Adar1 binding, probably through cytosine methylation-specific readers, such as RNA helicases. Our study reveals a previously unknown regulatory role of Tet2 at the epitranscriptomic level, promoting myelopoiesis during infection in the mammalian system by decreasing 5-mCs in mRNAs. Moreover, the inhibitory function of cytosine methylation on double-stranded RNA formation and Adar1 binding in mRNA reveals its new physiological role in the mammalian system.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature25434</identifier><identifier>PMID: 29364877</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 3' Untranslated regions ; 3' Untranslated Regions - genetics ; 5-Methylcytosine - analogs & derivatives ; 5-Methylcytosine - metabolism ; 631/250/262 ; 692/420/256 ; 96/95 ; Adenosine Deaminase - metabolism ; Animals ; Bone marrow ; Bone Marrow Cells - immunology ; Cytokines ; Cytosine ; DNA methylation ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - metabolism ; Double-stranded RNA ; Enzymatic activity ; Epigenesis, Genetic ; Epigenetics ; Female ; Gene expression ; Gene Expression Regulation ; Gene regulation ; Genomics ; Humanities and Social Sciences ; Immune response ; Immune system ; Immunity, Innate ; Infections ; Inflammation ; Inflammatory response ; letter ; Mammals ; Messenger RNA ; Methylation ; Mice ; multidisciplinary ; Mutation ; Myelopoiesis ; Myelopoiesis - genetics ; Neutrophils ; Nucleic Acid Conformation ; Oxidation ; Oxidation-Reduction ; Parasites ; Pathogens ; Physiological research ; Physiology ; Post-transcription ; Proteins ; Proto-Oncogene Proteins - deficiency ; Proto-Oncogene Proteins - metabolism ; Ribonucleic acid ; RNA ; RNA editing ; RNA modification ; RNA, Double-Stranded - chemistry ; RNA, Double-Stranded - genetics ; RNA, Double-Stranded - metabolism ; RNA, Messenger - chemistry ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Science ; Sepsis ; Sepsis - genetics ; Sepsis - microbiology ; Suppressor of Cytokine Signaling 3 Protein - genetics ; Transcriptome - genetics ; Translocation ; Tumor suppressor genes</subject><ispartof>Nature (London), 2018-02, Vol.554 (7690), p.123-127</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 1, 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c586t-28a083680fde4735ae4673a1feb9351e60ab3fc7926ef0972b1a788fa7f1c3813</citedby><cites>FETCH-LOGICAL-c586t-28a083680fde4735ae4673a1feb9351e60ab3fc7926ef0972b1a788fa7f1c3813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29364877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shen, Qicong</creatorcontrib><creatorcontrib>Zhang, Qian</creatorcontrib><creatorcontrib>Shi, Yang</creatorcontrib><creatorcontrib>Shi, Qingzhu</creatorcontrib><creatorcontrib>Jiang, Yanyan</creatorcontrib><creatorcontrib>Gu, Yan</creatorcontrib><creatorcontrib>Li, Zhiqing</creatorcontrib><creatorcontrib>Li, Xia</creatorcontrib><creatorcontrib>Zhao, Kai</creatorcontrib><creatorcontrib>Wang, Chunmei</creatorcontrib><creatorcontrib>Li, Nan</creatorcontrib><creatorcontrib>Cao, Xuetao</creatorcontrib><title>Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>A report of RNA 5-methylcytosine oxidation by mammalian Tet2, showing that Tet2 promotes infection-induced myelopoiesis in mice via a mechanism involving the repression of Socs3 mRNA, a previously unknown regulatory role of Tet2 at the epitranscriptomic level.
mRNA oxidation mediates response to infection
Messenger RNA (mRNA) can be modified biochemically without changing its ribonucleotide sequence. These mRNA modifications are essential for post-transcriptional regulation of gene expression. Xuetao Cao and colleagues report the oxidation of the RNA base 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) by the mammalian Tet2 enzyme. The authors also show that Tet2 promotes infection-induced myelopoiesis—generation of innate immune cells from the bone marrow—in mice. This effect occurs through a mechanism involving the destabilization of Socs3 mRNA caused by decreased levels of 5-mC. These findings highlight the role of epitranscriptome modifications in mammalian physiology.
Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation
1
. 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions
2
. The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins in
Drosophila
has been revealed more recently
3
,
4
. However, the turnover and function of 5-mC in mammalian mRNA have been largely unknown. Tet2 suppresses myeloid malignancies mostly in an enzymatic activity-dependent manner
5
, and is important in resolving inflammatory response in an enzymatic activity-independent way
6
. Myelopoiesis is a common host immune response in acute and chronic infections; however, its epigenetic mechanism needs to be identified. Here we demonstrate that Tet2 promotes infection-induced myelopoiesis in an mRNA oxidation-dependent manner through Adar1-mediated repression of Socs3 expression at the post-transcription level. Tet2 promotes both abdominal sepsis-induced emergency myelopoiesis and parasite-induced mast cell expansion through decreasing mRNA levels of Socs3, a key negative regulator of the JAK–STAT pathway that is critical for cytokine-induced myelopoiesis. Tet2 represses Socs3 expression through Adar1, which binds and destabilizes Socs3 mRNA in a RNA editing-independent manner. For the underlying mechanism of Tet2 regulation at the mRNA level, Tet2 mediates oxidation of 5-mC in mRNA. Tet2 deficiency leads to the transcriptome-wide appearance of methylated cytosines, including ones in the 3′ untranslated region of Socs3, which influences double-stranded RNA formation for Adar1 binding, probably through cytosine methylation-specific readers, such as RNA helicases. Our study reveals a previously unknown regulatory role of Tet2 at the epitranscriptomic level, promoting myelopoiesis during infection in the mammalian system by decreasing 5-mCs in mRNAs. Moreover, the inhibitory function of cytosine methylation on double-stranded RNA formation and Adar1 binding in mRNA reveals its new physiological role in the mammalian system.</description><subject>13/31</subject><subject>3' Untranslated regions</subject><subject>3' Untranslated Regions - genetics</subject><subject>5-Methylcytosine - analogs & derivatives</subject><subject>5-Methylcytosine - metabolism</subject><subject>631/250/262</subject><subject>692/420/256</subject><subject>96/95</subject><subject>Adenosine Deaminase - metabolism</subject><subject>Animals</subject><subject>Bone marrow</subject><subject>Bone Marrow Cells - immunology</subject><subject>Cytokines</subject><subject>Cytosine</subject><subject>DNA methylation</subject><subject>DNA-Binding Proteins - deficiency</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Double-stranded RNA</subject><subject>Enzymatic activity</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gene regulation</subject><subject>Genomics</subject><subject>Humanities and Social Sciences</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunity, Innate</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Inflammatory response</subject><subject>letter</subject><subject>Mammals</subject><subject>Messenger RNA</subject><subject>Methylation</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Myelopoiesis</subject><subject>Myelopoiesis - genetics</subject><subject>Neutrophils</subject><subject>Nucleic Acid Conformation</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Parasites</subject><subject>Pathogens</subject><subject>Physiological research</subject><subject>Physiology</subject><subject>Post-transcription</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - deficiency</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA editing</subject><subject>RNA modification</subject><subject>RNA, Double-Stranded - chemistry</subject><subject>RNA, Double-Stranded - genetics</subject><subject>RNA, Double-Stranded - metabolism</subject><subject>RNA, Messenger - chemistry</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Science</subject><subject>Sepsis</subject><subject>Sepsis - genetics</subject><subject>Sepsis - microbiology</subject><subject>Suppressor of Cytokine Signaling 3 Protein - genetics</subject><subject>Transcriptome - genetics</subject><subject>Translocation</subject><subject>Tumor suppressor genes</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpt0s-L1DAUB_AgijuOnrxLcS-Kds2PtkmPw-KPhUFhXc8hk750srRNN0lh9783ZVadkZJDIPnk8c3jIfSa4AuCmfg0qDh5oGXBiidoRQpe5UUl-FO0wpiKHAtWnaEXIdxijEvCi-fojNasKgTnK7S9gUiz0bveRQjZqOLetTBkdjCgo3VDbodm0tBk_QN0bnQWgg1Z3Hs3tfusv_6-ydy9bdRsX6JnRnUBXj3ua_Try-eby2_59sfXq8vNNtelqGJOhZpDCWwaKDgrFRQVZ4oY2NWsJFBhtWNG85pWYHDN6Y4oLoRR3BDNBGFr9O5QN-W-myBE2dugoevUAG4KktQ1IbzmNUv0_D966yY_pHSzKmhV4Fr8U63qQKa_u-iVnovKTUlTaCpS0DXKF1TqFnjVuQGMTccn_u2C16O9k8foYgGl1UBv9WLV9ycPkolwH1s1hSCvfl6f2g8Hq70LwYORo7e98g-SYDkPjzwanqTfPPZq2vXQ_LV_piWBjwcQ0tXQgj9q5kK938mny0o</recordid><startdate>20180201</startdate><enddate>20180201</enddate><creator>Shen, Qicong</creator><creator>Zhang, Qian</creator><creator>Shi, Yang</creator><creator>Shi, Qingzhu</creator><creator>Jiang, Yanyan</creator><creator>Gu, Yan</creator><creator>Li, Zhiqing</creator><creator>Li, Xia</creator><creator>Zhao, Kai</creator><creator>Wang, Chunmei</creator><creator>Li, Nan</creator><creator>Cao, Xuetao</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7X8</scope></search><sort><creationdate>20180201</creationdate><title>Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation</title><author>Shen, Qicong ; Zhang, Qian ; Shi, Yang ; Shi, Qingzhu ; Jiang, Yanyan ; Gu, Yan ; Li, Zhiqing ; Li, Xia ; Zhao, Kai ; Wang, Chunmei ; Li, Nan ; Cao, Xuetao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c586t-28a083680fde4735ae4673a1feb9351e60ab3fc7926ef0972b1a788fa7f1c3813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13/31</topic><topic>3' Untranslated regions</topic><topic>3' Untranslated Regions - genetics</topic><topic>5-Methylcytosine - analogs & derivatives</topic><topic>5-Methylcytosine - metabolism</topic><topic>631/250/262</topic><topic>692/420/256</topic><topic>96/95</topic><topic>Adenosine Deaminase - metabolism</topic><topic>Animals</topic><topic>Bone marrow</topic><topic>Bone Marrow Cells - immunology</topic><topic>Cytokines</topic><topic>Cytosine</topic><topic>DNA methylation</topic><topic>DNA-Binding Proteins - deficiency</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Double-stranded RNA</topic><topic>Enzymatic activity</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Gene regulation</topic><topic>Genomics</topic><topic>Humanities and Social Sciences</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunity, Innate</topic><topic>Infections</topic><topic>Inflammation</topic><topic>Inflammatory response</topic><topic>letter</topic><topic>Mammals</topic><topic>Messenger RNA</topic><topic>Methylation</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Myelopoiesis</topic><topic>Myelopoiesis - genetics</topic><topic>Neutrophils</topic><topic>Nucleic Acid Conformation</topic><topic>Oxidation</topic><topic>Oxidation-Reduction</topic><topic>Parasites</topic><topic>Pathogens</topic><topic>Physiological research</topic><topic>Physiology</topic><topic>Post-transcription</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - deficiency</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA editing</topic><topic>RNA modification</topic><topic>RNA, Double-Stranded - chemistry</topic><topic>RNA, Double-Stranded - genetics</topic><topic>RNA, Double-Stranded - metabolism</topic><topic>RNA, Messenger - chemistry</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Science</topic><topic>Sepsis</topic><topic>Sepsis - genetics</topic><topic>Sepsis - microbiology</topic><topic>Suppressor of Cytokine Signaling 3 Protein - genetics</topic><topic>Transcriptome - genetics</topic><topic>Translocation</topic><topic>Tumor suppressor genes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shen, Qicong</creatorcontrib><creatorcontrib>Zhang, Qian</creatorcontrib><creatorcontrib>Shi, Yang</creatorcontrib><creatorcontrib>Shi, Qingzhu</creatorcontrib><creatorcontrib>Jiang, Yanyan</creatorcontrib><creatorcontrib>Gu, Yan</creatorcontrib><creatorcontrib>Li, Zhiqing</creatorcontrib><creatorcontrib>Li, Xia</creatorcontrib><creatorcontrib>Zhao, Kai</creatorcontrib><creatorcontrib>Wang, Chunmei</creatorcontrib><creatorcontrib>Li, Nan</creatorcontrib><creatorcontrib>Cao, Xuetao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Earth, Atmospheric & Aquatic Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Psychology Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shen, Qicong</au><au>Zhang, Qian</au><au>Shi, Yang</au><au>Shi, Qingzhu</au><au>Jiang, Yanyan</au><au>Gu, Yan</au><au>Li, Zhiqing</au><au>Li, Xia</au><au>Zhao, Kai</au><au>Wang, Chunmei</au><au>Li, Nan</au><au>Cao, Xuetao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2018-02-01</date><risdate>2018</risdate><volume>554</volume><issue>7690</issue><spage>123</spage><epage>127</epage><pages>123-127</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>A report of RNA 5-methylcytosine oxidation by mammalian Tet2, showing that Tet2 promotes infection-induced myelopoiesis in mice via a mechanism involving the repression of Socs3 mRNA, a previously unknown regulatory role of Tet2 at the epitranscriptomic level.
mRNA oxidation mediates response to infection
Messenger RNA (mRNA) can be modified biochemically without changing its ribonucleotide sequence. These mRNA modifications are essential for post-transcriptional regulation of gene expression. Xuetao Cao and colleagues report the oxidation of the RNA base 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) by the mammalian Tet2 enzyme. The authors also show that Tet2 promotes infection-induced myelopoiesis—generation of innate immune cells from the bone marrow—in mice. This effect occurs through a mechanism involving the destabilization of Socs3 mRNA caused by decreased levels of 5-mC. These findings highlight the role of epitranscriptome modifications in mammalian physiology.
Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation
1
. 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions
2
. The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins in
Drosophila
has been revealed more recently
3
,
4
. However, the turnover and function of 5-mC in mammalian mRNA have been largely unknown. Tet2 suppresses myeloid malignancies mostly in an enzymatic activity-dependent manner
5
, and is important in resolving inflammatory response in an enzymatic activity-independent way
6
. Myelopoiesis is a common host immune response in acute and chronic infections; however, its epigenetic mechanism needs to be identified. Here we demonstrate that Tet2 promotes infection-induced myelopoiesis in an mRNA oxidation-dependent manner through Adar1-mediated repression of Socs3 expression at the post-transcription level. Tet2 promotes both abdominal sepsis-induced emergency myelopoiesis and parasite-induced mast cell expansion through decreasing mRNA levels of Socs3, a key negative regulator of the JAK–STAT pathway that is critical for cytokine-induced myelopoiesis. Tet2 represses Socs3 expression through Adar1, which binds and destabilizes Socs3 mRNA in a RNA editing-independent manner. For the underlying mechanism of Tet2 regulation at the mRNA level, Tet2 mediates oxidation of 5-mC in mRNA. Tet2 deficiency leads to the transcriptome-wide appearance of methylated cytosines, including ones in the 3′ untranslated region of Socs3, which influences double-stranded RNA formation for Adar1 binding, probably through cytosine methylation-specific readers, such as RNA helicases. Our study reveals a previously unknown regulatory role of Tet2 at the epitranscriptomic level, promoting myelopoiesis during infection in the mammalian system by decreasing 5-mCs in mRNAs. Moreover, the inhibitory function of cytosine methylation on double-stranded RNA formation and Adar1 binding in mRNA reveals its new physiological role in the mammalian system.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29364877</pmid><doi>10.1038/nature25434</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2018-02, Vol.554 (7690), p.123-127 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1991179793 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 13/31 3' Untranslated regions 3' Untranslated Regions - genetics 5-Methylcytosine - analogs & derivatives 5-Methylcytosine - metabolism 631/250/262 692/420/256 96/95 Adenosine Deaminase - metabolism Animals Bone marrow Bone Marrow Cells - immunology Cytokines Cytosine DNA methylation DNA-Binding Proteins - deficiency DNA-Binding Proteins - metabolism Double-stranded RNA Enzymatic activity Epigenesis, Genetic Epigenetics Female Gene expression Gene Expression Regulation Gene regulation Genomics Humanities and Social Sciences Immune response Immune system Immunity, Innate Infections Inflammation Inflammatory response letter Mammals Messenger RNA Methylation Mice multidisciplinary Mutation Myelopoiesis Myelopoiesis - genetics Neutrophils Nucleic Acid Conformation Oxidation Oxidation-Reduction Parasites Pathogens Physiological research Physiology Post-transcription Proteins Proto-Oncogene Proteins - deficiency Proto-Oncogene Proteins - metabolism Ribonucleic acid RNA RNA editing RNA modification RNA, Double-Stranded - chemistry RNA, Double-Stranded - genetics RNA, Double-Stranded - metabolism RNA, Messenger - chemistry RNA, Messenger - genetics RNA, Messenger - metabolism Science Sepsis Sepsis - genetics Sepsis - microbiology Suppressor of Cytokine Signaling 3 Protein - genetics Transcriptome - genetics Translocation Tumor suppressor genes |
| title | Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T15%3A47%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Tet2%20promotes%20pathogen%20infection-induced%20myelopoiesis%20through%20mRNA%20oxidation&rft.jtitle=Nature%20(London)&rft.au=Shen,%20Qicong&rft.date=2018-02-01&rft.volume=554&rft.issue=7690&rft.spage=123&rft.epage=127&rft.pages=123-127&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/nature25434&rft_dat=%3Cgale_proqu%3EA525862847%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1994264098&rft_id=info:pmid/29364877&rft_galeid=A525862847&rfr_iscdi=true |