Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging
The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs...
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| Veröffentlicht in: | Cell stem cell 2013-04, Vol.12 (4), p.413-425 |
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| creator | Beerman, Isabel Bock, Christoph Garrison, Brian S. Smith, Zachary D. Gu, Hongcang Meissner, Alexander Rossi, Derrick J. |
| description | The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging.
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► Locus-specific alterations of the DNA methylome accompany HSC aging ► Methylation changes target genes expressed downstream of HSCs to alter HSC potential ► HSC potential, DNA methylation, and replicative limits depend on divisional history ► Aging and forced proliferation of HSC results in DNA hypermethylation of PRC2 targets
Functional decline of hematopoietic stem cells during aging is linked to proliferation-dependent changes in DNA methylation. |
| doi_str_mv | 10.1016/j.stem.2013.01.017 |
| format | Article |
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[Display omitted]
► Locus-specific alterations of the DNA methylome accompany HSC aging ► Methylation changes target genes expressed downstream of HSCs to alter HSC potential ► HSC potential, DNA methylation, and replicative limits depend on divisional history ► Aging and forced proliferation of HSC results in DNA hypermethylation of PRC2 targets
Functional decline of hematopoietic stem cells during aging is linked to proliferation-dependent changes in DNA methylation.</description><identifier>ISSN: 1934-5909</identifier><identifier>EISSN: 1875-9777</identifier><identifier>DOI: 10.1016/j.stem.2013.01.017</identifier><identifier>PMID: 23415915</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cell Proliferation ; Cellular Senescence - genetics ; DNA Methylation - genetics ; DNA Replication - genetics ; Gene Expression Regulation, Developmental ; Hematopoiesis - genetics ; Hematopoietic Stem Cells - cytology ; Hematopoietic Stem Cells - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Polycomb Repressive Complex 2 - metabolism ; Telomere - metabolism</subject><ispartof>Cell stem cell, 2013-04, Vol.12 (4), p.413-425</ispartof><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-3ed4f7fc007882ed2bbd801c7a9a9a82bfe8ee6fce31e2dc6cffc2a28cd677d03</citedby><cites>FETCH-LOGICAL-c499t-3ed4f7fc007882ed2bbd801c7a9a9a82bfe8ee6fce31e2dc6cffc2a28cd677d03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1934590913000209$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23415915$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Beerman, Isabel</creatorcontrib><creatorcontrib>Bock, Christoph</creatorcontrib><creatorcontrib>Garrison, Brian S.</creatorcontrib><creatorcontrib>Smith, Zachary D.</creatorcontrib><creatorcontrib>Gu, Hongcang</creatorcontrib><creatorcontrib>Meissner, Alexander</creatorcontrib><creatorcontrib>Rossi, Derrick J.</creatorcontrib><title>Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging</title><title>Cell stem cell</title><addtitle>Cell Stem Cell</addtitle><description>The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging.
[Display omitted]
► Locus-specific alterations of the DNA methylome accompany HSC aging ► Methylation changes target genes expressed downstream of HSCs to alter HSC potential ► HSC potential, DNA methylation, and replicative limits depend on divisional history ► Aging and forced proliferation of HSC results in DNA hypermethylation of PRC2 targets
Functional decline of hematopoietic stem cells during aging is linked to proliferation-dependent changes in DNA methylation.</description><subject>Animals</subject><subject>Cell Proliferation</subject><subject>Cellular Senescence - genetics</subject><subject>DNA Methylation - genetics</subject><subject>DNA Replication - genetics</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Hematopoiesis - genetics</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Biological</subject><subject>Polycomb Repressive Complex 2 - metabolism</subject><subject>Telomere - metabolism</subject><issn>1934-5909</issn><issn>1875-9777</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkVtrGzEQhUVoya39A30oeuzLOrrsWhL0xThXcC_Q5lnI0iiRu7vaSnIg_z5y7PaxlBkYMXznMOgg9IGSGSV0frGZ5QLDjBHKZ4TWFkfolErRNUoI8aa-FW-bThF1gs5y3hDSCUrEMTphvKWdot0p-vU9xT54SKaEODaXMMHoYCx40ZfDMuPocXkEfPl1gb9AeXzuX_d4ZUaXrZkA31dN6gPgWxhMiVMMUILFP-p5eAl9jxcPYXx4h95602d4f5jn6P766ufytll9u7lbLlaNbZUqDQfXeuEtIUJKBo6t104SaoVRtSRbe5AAc2-BU2DOzq33lhkmrZsL4Qg_R5_2vlOKv7eQix5CtvUMM0LcZk15K1speMf-A2Wt6qTksqJsj9oUc07g9ZTCYNKzpkTv8tAbvctD7_LQhNYWVfTx4L9dD-D-Sv4EUIHPewDqhzwFSDrbAKMFFxLYol0M__J_AXJwnhk</recordid><startdate>20130404</startdate><enddate>20130404</enddate><creator>Beerman, Isabel</creator><creator>Bock, Christoph</creator><creator>Garrison, Brian S.</creator><creator>Smith, Zachary D.</creator><creator>Gu, Hongcang</creator><creator>Meissner, Alexander</creator><creator>Rossi, Derrick J.</creator><general>Elsevier Inc</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>7X8</scope><scope>7QO</scope><scope>7T5</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20130404</creationdate><title>Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging</title><author>Beerman, Isabel ; Bock, Christoph ; Garrison, Brian S. ; Smith, Zachary D. ; Gu, Hongcang ; Meissner, Alexander ; Rossi, Derrick J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-3ed4f7fc007882ed2bbd801c7a9a9a82bfe8ee6fce31e2dc6cffc2a28cd677d03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Cell Proliferation</topic><topic>Cellular Senescence - genetics</topic><topic>DNA Methylation - genetics</topic><topic>DNA Replication - genetics</topic><topic>Gene Expression Regulation, Developmental</topic><topic>Hematopoiesis - genetics</topic><topic>Hematopoietic Stem Cells - cytology</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Biological</topic><topic>Polycomb Repressive Complex 2 - metabolism</topic><topic>Telomere - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Beerman, Isabel</creatorcontrib><creatorcontrib>Bock, Christoph</creatorcontrib><creatorcontrib>Garrison, Brian S.</creatorcontrib><creatorcontrib>Smith, Zachary D.</creatorcontrib><creatorcontrib>Gu, Hongcang</creatorcontrib><creatorcontrib>Meissner, Alexander</creatorcontrib><creatorcontrib>Rossi, Derrick J.</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>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Cell stem cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Beerman, Isabel</au><au>Bock, Christoph</au><au>Garrison, Brian S.</au><au>Smith, Zachary D.</au><au>Gu, Hongcang</au><au>Meissner, Alexander</au><au>Rossi, Derrick J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging</atitle><jtitle>Cell stem cell</jtitle><addtitle>Cell Stem Cell</addtitle><date>2013-04-04</date><risdate>2013</risdate><volume>12</volume><issue>4</issue><spage>413</spage><epage>425</epage><pages>413-425</pages><issn>1934-5909</issn><eissn>1875-9777</eissn><abstract>The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging.
[Display omitted]
► Locus-specific alterations of the DNA methylome accompany HSC aging ► Methylation changes target genes expressed downstream of HSCs to alter HSC potential ► HSC potential, DNA methylation, and replicative limits depend on divisional history ► Aging and forced proliferation of HSC results in DNA hypermethylation of PRC2 targets
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| subjects | Animals Cell Proliferation Cellular Senescence - genetics DNA Methylation - genetics DNA Replication - genetics Gene Expression Regulation, Developmental Hematopoiesis - genetics Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - metabolism Male Mice Mice, Inbred C57BL Models, Biological Polycomb Repressive Complex 2 - metabolism Telomere - metabolism |
| title | Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging |
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