The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression
MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpres...
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creator | Mehta, Arnav Zhao, Jimmy L. Sinha, Nikita Marinov, Georgi K. Mann, Mati Kowalczyk, Monika S. Galimidi, Rachel P. Du, Xiaomi Erikci, Erdem Regev, Aviv Chowdhury, Kamal Baltimore, David |
description | MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects.
•The miR-212/132 cluster (Mirc19) is enriched in HSCs and upregulated with age•Mirc19 regulates HSC cycling, function, and survival through autophagy•Enforced expression or deletion of Mirc19 leads to inappropriate hematopoiesis•miR-132 directly targets FOXO3 and buffers its expression in aging HSCs
Aging hematopoietic stem cells (HSCs) must maintain normal hematopoietic output despite years of replication stress. Baltimore and colleagues show that microRNA-132 helps maintain the balance of HSC survival and normal immune cell production by buffering the transcription factor FOXO3, a known regulator of HSC cycling, function, and survival. |
doi_str_mv | 10.1016/j.immuni.2015.05.017 |
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•The miR-212/132 cluster (Mirc19) is enriched in HSCs and upregulated with age•Mirc19 regulates HSC cycling, function, and survival through autophagy•Enforced expression or deletion of Mirc19 leads to inappropriate hematopoiesis•miR-132 directly targets FOXO3 and buffers its expression in aging HSCs
Aging hematopoietic stem cells (HSCs) must maintain normal hematopoietic output despite years of replication stress. Baltimore and colleagues show that microRNA-132 helps maintain the balance of HSC survival and normal immune cell production by buffering the transcription factor FOXO3, a known regulator of HSC cycling, function, and survival.</description><identifier>ISSN: 1074-7613</identifier><identifier>EISSN: 1097-4180</identifier><identifier>DOI: 10.1016/j.immuni.2015.05.017</identifier><identifier>PMID: 26084022</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Age ; Aging - genetics ; Animals ; Apoptosis - genetics ; Autophagy ; Bone marrow ; Bone Marrow Cells - physiology ; Cell Differentiation - genetics ; Cell Line ; Cell Survival - genetics ; Flow cytometry ; Forkhead Box Protein O3 ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Gene expression ; Gene Expression Regulation ; Hematopoiesis - genetics ; Hematopoietic Stem Cells - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Stem Cell Factor - metabolism ; Stem cells ; Studies</subject><ispartof>Immunity (Cambridge, Mass.), 2015-06, Vol.42 (6), p.1021-1032</ispartof><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Jun 16, 2015</rights><rights>2015 Published by Elsevier Inc. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-2fa54c6985a04d1ae891927a4f49725ecf37d495b7209e165d423d06d6948da73</citedby><cites>FETCH-LOGICAL-c524t-2fa54c6985a04d1ae891927a4f49725ecf37d495b7209e165d423d06d6948da73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1074761315002150$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26084022$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mehta, Arnav</creatorcontrib><creatorcontrib>Zhao, Jimmy L.</creatorcontrib><creatorcontrib>Sinha, Nikita</creatorcontrib><creatorcontrib>Marinov, Georgi K.</creatorcontrib><creatorcontrib>Mann, Mati</creatorcontrib><creatorcontrib>Kowalczyk, Monika S.</creatorcontrib><creatorcontrib>Galimidi, Rachel P.</creatorcontrib><creatorcontrib>Du, Xiaomi</creatorcontrib><creatorcontrib>Erikci, Erdem</creatorcontrib><creatorcontrib>Regev, Aviv</creatorcontrib><creatorcontrib>Chowdhury, Kamal</creatorcontrib><creatorcontrib>Baltimore, David</creatorcontrib><title>The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression</title><title>Immunity (Cambridge, Mass.)</title><addtitle>Immunity</addtitle><description>MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects.
•The miR-212/132 cluster (Mirc19) is enriched in HSCs and upregulated with age•Mirc19 regulates HSC cycling, function, and survival through autophagy•Enforced expression or deletion of Mirc19 leads to inappropriate hematopoiesis•miR-132 directly targets FOXO3 and buffers its expression in aging HSCs
Aging hematopoietic stem cells (HSCs) must maintain normal hematopoietic output despite years of replication stress. Baltimore and colleagues show that microRNA-132 helps maintain the balance of HSC survival and normal immune cell production by buffering the transcription factor FOXO3, a known regulator of HSC cycling, function, and survival.</description><subject>Age</subject><subject>Aging - genetics</subject><subject>Animals</subject><subject>Apoptosis - genetics</subject><subject>Autophagy</subject><subject>Bone marrow</subject><subject>Bone Marrow Cells - physiology</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Line</subject><subject>Cell Survival - genetics</subject><subject>Flow cytometry</subject><subject>Forkhead Box Protein O3</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Hematopoiesis - genetics</subject><subject>Hematopoietic Stem Cells - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>Stem Cell Factor - metabolism</subject><subject>Stem cells</subject><subject>Studies</subject><issn>1074-7613</issn><issn>1097-4180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUsFu1DAQjRCIlsIfIGSJC5cstmPH8QWprFqK1LJSWyRultee7HqV2FvbWeg38NMkbGmBA0gj2fK8eeN584riJcEzgkn9djNzfT94N6OY8Bkeg4hHxSHBUpSMNPjxdBesFDWpDopnKW0wJoxL_LQ4oDVuGKb0sPh-vQZ04UwMl5-OS1JRpL19eKCEonk3pAwRXcJq6HSGhM6g1zlsg4PsDLrK0KM5dB260M5n8Nob-ElzNcSd2-kOfXV5jY5XgJa36P3QthCdX6HTxZdFhU6-bSOk5IJ_XjxpdZfgxd15VHw-Pbmen5Xniw8f58fnpeGU5ZK2mjNTy4ZrzCzR0EgiqdCsZVJQDqathGWSLwXFEkjNLaOVxbWtJWusFtVR8W7Pux2WPVgDPkfdqW10vY63Kmin_sx4t1arsFOMCdKIieDNHUEMNwOkrHqXzKiA9hCGpIgYlW4Yk-z_0FpiSjCvJujrv6CbMEQ_KjGiGllxSeXUm-1R44ZSitDe_5tgNRlDbdTeGGoyhsJjkKns1e8z3xf9csKDKDAqv3MQVTIOxk1aF8FkZYP7d4cfen3KIg</recordid><startdate>20150616</startdate><enddate>20150616</enddate><creator>Mehta, Arnav</creator><creator>Zhao, Jimmy L.</creator><creator>Sinha, Nikita</creator><creator>Marinov, Georgi K.</creator><creator>Mann, Mati</creator><creator>Kowalczyk, Monika S.</creator><creator>Galimidi, Rachel P.</creator><creator>Du, Xiaomi</creator><creator>Erikci, Erdem</creator><creator>Regev, Aviv</creator><creator>Chowdhury, Kamal</creator><creator>Baltimore, David</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150616</creationdate><title>The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression</title><author>Mehta, Arnav ; Zhao, Jimmy L. ; Sinha, Nikita ; Marinov, Georgi K. ; Mann, Mati ; Kowalczyk, Monika S. ; Galimidi, Rachel P. ; Du, Xiaomi ; Erikci, Erdem ; Regev, Aviv ; Chowdhury, Kamal ; Baltimore, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-2fa54c6985a04d1ae891927a4f49725ecf37d495b7209e165d423d06d6948da73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Age</topic><topic>Aging - genetics</topic><topic>Animals</topic><topic>Apoptosis - genetics</topic><topic>Autophagy</topic><topic>Bone marrow</topic><topic>Bone Marrow Cells - physiology</topic><topic>Cell Differentiation - genetics</topic><topic>Cell Line</topic><topic>Cell Survival - genetics</topic><topic>Flow cytometry</topic><topic>Forkhead Box Protein O3</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Hematopoiesis - genetics</topic><topic>Hematopoietic Stem Cells - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>Stem Cell Factor - metabolism</topic><topic>Stem cells</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mehta, Arnav</creatorcontrib><creatorcontrib>Zhao, Jimmy L.</creatorcontrib><creatorcontrib>Sinha, Nikita</creatorcontrib><creatorcontrib>Marinov, Georgi K.</creatorcontrib><creatorcontrib>Mann, Mati</creatorcontrib><creatorcontrib>Kowalczyk, Monika S.</creatorcontrib><creatorcontrib>Galimidi, Rachel P.</creatorcontrib><creatorcontrib>Du, Xiaomi</creatorcontrib><creatorcontrib>Erikci, Erdem</creatorcontrib><creatorcontrib>Regev, Aviv</creatorcontrib><creatorcontrib>Chowdhury, Kamal</creatorcontrib><creatorcontrib>Baltimore, David</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect: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>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Immunity (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mehta, Arnav</au><au>Zhao, Jimmy L.</au><au>Sinha, Nikita</au><au>Marinov, Georgi K.</au><au>Mann, Mati</au><au>Kowalczyk, Monika S.</au><au>Galimidi, Rachel P.</au><au>Du, Xiaomi</au><au>Erikci, Erdem</au><au>Regev, Aviv</au><au>Chowdhury, Kamal</au><au>Baltimore, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression</atitle><jtitle>Immunity (Cambridge, Mass.)</jtitle><addtitle>Immunity</addtitle><date>2015-06-16</date><risdate>2015</risdate><volume>42</volume><issue>6</issue><spage>1021</spage><epage>1032</epage><pages>1021-1032</pages><issn>1074-7613</issn><eissn>1097-4180</eissn><abstract>MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects.
•The miR-212/132 cluster (Mirc19) is enriched in HSCs and upregulated with age•Mirc19 regulates HSC cycling, function, and survival through autophagy•Enforced expression or deletion of Mirc19 leads to inappropriate hematopoiesis•miR-132 directly targets FOXO3 and buffers its expression in aging HSCs
Aging hematopoietic stem cells (HSCs) must maintain normal hematopoietic output despite years of replication stress. Baltimore and colleagues show that microRNA-132 helps maintain the balance of HSC survival and normal immune cell production by buffering the transcription factor FOXO3, a known regulator of HSC cycling, function, and survival.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26084022</pmid><doi>10.1016/j.immuni.2015.05.017</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Age Aging - genetics Animals Apoptosis - genetics Autophagy Bone marrow Bone Marrow Cells - physiology Cell Differentiation - genetics Cell Line Cell Survival - genetics Flow cytometry Forkhead Box Protein O3 Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Gene expression Gene Expression Regulation Hematopoiesis - genetics Hematopoietic Stem Cells - physiology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Stem Cell Factor - metabolism Stem cells Studies |
title | The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression |
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