Decoding the Regulatory Landscape of Ageing in Musculoskeletal Engineered Tissues Using Genome-Wide DNA Methylation and RNASeq
Mesenchymal stem cells (MSC) are capable of multipotent differentiation into connective tissues and as such are an attractive source for autologous cell-based regenerative medicine and tissue engineering. Epigenetic mechanisms, like DNA methylation, contribute to the changes in gene expression in ag...
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| description | Mesenchymal stem cells (MSC) are capable of multipotent differentiation into connective tissues and as such are an attractive source for autologous cell-based regenerative medicine and tissue engineering. Epigenetic mechanisms, like DNA methylation, contribute to the changes in gene expression in ageing. However there was a lack of sufficient knowledge of the role that differential methylation plays during chondrogenic, osteogenic and tenogenic differentiation from ageing MSCs. This study undertook genome level determination of the effects of DNA methylation on expression in engineered tissues from chronologically aged MSCs. We compiled unique DNA methylation signatures from chondrogenic, osteogenic, and tenogenic engineered tissues derived from young; n = 4 (21.8 years ± 2.4 SD) and old; n = 4 (65.5 years±8.3SD) human MSCs donors using the Illumina HumanMethylation 450 Beadchip arrays and compared these to gene expression by RNA sequencing. Unique and common signatures of global DNA methylation were identified. There were 201, 67 and 32 chondrogenic, osteogenic and tenogenic age-related DE protein-coding genes respectively. Findings inferred the nature of the transcript networks was predominantly for 'cell death and survival', 'cell morphology', and 'cell growth and proliferation'. Further studies are required to validate if this gene expression effect translates to cell events. Alternative splicing (AS) was dysregulated in ageing with 119, 21 and 9 differential splicing events identified in chondrogenic, osteogenic and tenogenic respectively, and enrichment in genes associated principally with metabolic processes. Gene ontology analysis of differentially methylated loci indicated age-related enrichment for all engineered tissue types in 'skeletal system morphogenesis', 'regulation of cell proliferation' and 'regulation of transcription' suggesting that dynamic epigenetic modifications may occur in genes associated with shared and distinct pathways dependent upon engineered tissue type. An altered phenotype in engineered tissues was observed with ageing at numerous levels. These changes represent novel insights into the ageing process, with implications for stem cell therapies in older patients. In addition we have identified a number of tissue-dependant pathways, which warrant further studies. |
| doi_str_mv | 10.1371/journal.pone.0160517 |
| format | Article |
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Epigenetic mechanisms, like DNA methylation, contribute to the changes in gene expression in ageing. However there was a lack of sufficient knowledge of the role that differential methylation plays during chondrogenic, osteogenic and tenogenic differentiation from ageing MSCs. This study undertook genome level determination of the effects of DNA methylation on expression in engineered tissues from chronologically aged MSCs. We compiled unique DNA methylation signatures from chondrogenic, osteogenic, and tenogenic engineered tissues derived from young; n = 4 (21.8 years ± 2.4 SD) and old; n = 4 (65.5 years±8.3SD) human MSCs donors using the Illumina HumanMethylation 450 Beadchip arrays and compared these to gene expression by RNA sequencing. Unique and common signatures of global DNA methylation were identified. There were 201, 67 and 32 chondrogenic, osteogenic and tenogenic age-related DE protein-coding genes respectively. Findings inferred the nature of the transcript networks was predominantly for 'cell death and survival', 'cell morphology', and 'cell growth and proliferation'. Further studies are required to validate if this gene expression effect translates to cell events. Alternative splicing (AS) was dysregulated in ageing with 119, 21 and 9 differential splicing events identified in chondrogenic, osteogenic and tenogenic respectively, and enrichment in genes associated principally with metabolic processes. Gene ontology analysis of differentially methylated loci indicated age-related enrichment for all engineered tissue types in 'skeletal system morphogenesis', 'regulation of cell proliferation' and 'regulation of transcription' suggesting that dynamic epigenetic modifications may occur in genes associated with shared and distinct pathways dependent upon engineered tissue type. An altered phenotype in engineered tissues was observed with ageing at numerous levels. These changes represent novel insights into the ageing process, with implications for stem cell therapies in older patients. In addition we have identified a number of tissue-dependant pathways, which warrant further studies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0160517</identifier><identifier>PMID: 27533049</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aged ; Aging - genetics ; Aging - pathology ; Alternative Splicing ; Analysis ; Arthritis ; Autografts ; Biocompatibility ; Biology and life sciences ; Biomedical materials ; Cell death ; Cell Differentiation ; Cell morphology ; Cell Proliferation ; Cell survival ; Cells, Cultured ; Chondrogenesis - genetics ; Chronic illnesses ; Connective tissues ; Cytology ; Decoding ; Deoxyribonucleic acid ; Differentiation ; DNA ; DNA Methylation ; DNA sequencing ; Engineering and Technology ; Enrichment ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Gene expression ; Gene regulation ; Gene Regulatory Networks ; Gene sequencing ; Genes ; Genetic aspects ; Genomes ; Humans ; Medicine and Health Sciences ; Mesenchymal Stem Cells - cytology ; Mesenchymal Stem Cells - metabolism ; Mesenchyme ; Methylation ; Middle Aged ; Morphogenesis ; Musculoskeletal System - metabolism ; Musculoskeletal System - pathology ; Oligonucleotide Array Sequence Analysis ; Osteogenesis - genetics ; Physiological aspects ; Regenerative Medicine ; Ribonucleic acid ; RNA ; RNA sequencing ; Sequence Analysis, RNA ; Signatures ; Skeletal system ; Stem cells ; Studies ; Tendons - cytology ; Tendons - metabolism ; Tissue engineering ; Tissue Engineering - methods ; Transcription ; Young Adult</subject><ispartof>PloS one, 2016-08, Vol.11 (8), p.e0160517-e0160517</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Peffers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Peffers et al 2016 Peffers et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-b450f49793a13598e1b3d830ce12b02d386c55dee347685eb3914108179d8df03</citedby><cites>FETCH-LOGICAL-c725t-b450f49793a13598e1b3d830ce12b02d386c55dee347685eb3914108179d8df03</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/PMC4988628/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988628/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23853,27911,27912,53778,53780,79355,79356</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27533049$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gronthos, Stan</contributor><creatorcontrib>Peffers, Mandy Jayne</creatorcontrib><creatorcontrib>Goljanek-Whysall, Katarzyna</creatorcontrib><creatorcontrib>Collins, John</creatorcontrib><creatorcontrib>Fang, Yongxiang</creatorcontrib><creatorcontrib>Rushton, Michael</creatorcontrib><creatorcontrib>Loughlin, John</creatorcontrib><creatorcontrib>Proctor, Carole</creatorcontrib><creatorcontrib>Clegg, Peter David</creatorcontrib><title>Decoding the Regulatory Landscape of Ageing in Musculoskeletal Engineered Tissues Using Genome-Wide DNA Methylation and RNASeq</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Mesenchymal stem cells (MSC) are capable of multipotent differentiation into connective tissues and as such are an attractive source for autologous cell-based regenerative medicine and tissue engineering. Epigenetic mechanisms, like DNA methylation, contribute to the changes in gene expression in ageing. However there was a lack of sufficient knowledge of the role that differential methylation plays during chondrogenic, osteogenic and tenogenic differentiation from ageing MSCs. This study undertook genome level determination of the effects of DNA methylation on expression in engineered tissues from chronologically aged MSCs. We compiled unique DNA methylation signatures from chondrogenic, osteogenic, and tenogenic engineered tissues derived from young; n = 4 (21.8 years ± 2.4 SD) and old; n = 4 (65.5 years±8.3SD) human MSCs donors using the Illumina HumanMethylation 450 Beadchip arrays and compared these to gene expression by RNA sequencing. Unique and common signatures of global DNA methylation were identified. There were 201, 67 and 32 chondrogenic, osteogenic and tenogenic age-related DE protein-coding genes respectively. Findings inferred the nature of the transcript networks was predominantly for 'cell death and survival', 'cell morphology', and 'cell growth and proliferation'. Further studies are required to validate if this gene expression effect translates to cell events. Alternative splicing (AS) was dysregulated in ageing with 119, 21 and 9 differential splicing events identified in chondrogenic, osteogenic and tenogenic respectively, and enrichment in genes associated principally with metabolic processes. Gene ontology analysis of differentially methylated loci indicated age-related enrichment for all engineered tissue types in 'skeletal system morphogenesis', 'regulation of cell proliferation' and 'regulation of transcription' suggesting that dynamic epigenetic modifications may occur in genes associated with shared and distinct pathways dependent upon engineered tissue type. An altered phenotype in engineered tissues was observed with ageing at numerous levels. These changes represent novel insights into the ageing process, with implications for stem cell therapies in older patients. In addition we have identified a number of tissue-dependant pathways, which warrant further studies.</description><subject>Aged</subject><subject>Aging - genetics</subject><subject>Aging - pathology</subject><subject>Alternative Splicing</subject><subject>Analysis</subject><subject>Arthritis</subject><subject>Autografts</subject><subject>Biocompatibility</subject><subject>Biology and life sciences</subject><subject>Biomedical materials</subject><subject>Cell death</subject><subject>Cell Differentiation</subject><subject>Cell morphology</subject><subject>Cell Proliferation</subject><subject>Cell survival</subject><subject>Cells, Cultured</subject><subject>Chondrogenesis - genetics</subject><subject>Chronic illnesses</subject><subject>Connective tissues</subject><subject>Cytology</subject><subject>Decoding</subject><subject>Deoxyribonucleic acid</subject><subject>Differentiation</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA sequencing</subject><subject>Engineering and Technology</subject><subject>Enrichment</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Gene Regulatory Networks</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Humans</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchymal Stem Cells - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Peffers, Mandy Jayne</au><au>Goljanek-Whysall, Katarzyna</au><au>Collins, John</au><au>Fang, Yongxiang</au><au>Rushton, Michael</au><au>Loughlin, John</au><au>Proctor, Carole</au><au>Clegg, Peter David</au><au>Gronthos, Stan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Decoding the Regulatory Landscape of Ageing in Musculoskeletal Engineered Tissues Using Genome-Wide DNA Methylation and RNASeq</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-08-17</date><risdate>2016</risdate><volume>11</volume><issue>8</issue><spage>e0160517</spage><epage>e0160517</epage><pages>e0160517-e0160517</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Mesenchymal stem cells (MSC) are capable of multipotent differentiation into connective tissues and as such are an attractive source for autologous cell-based regenerative medicine and tissue engineering. Epigenetic mechanisms, like DNA methylation, contribute to the changes in gene expression in ageing. However there was a lack of sufficient knowledge of the role that differential methylation plays during chondrogenic, osteogenic and tenogenic differentiation from ageing MSCs. This study undertook genome level determination of the effects of DNA methylation on expression in engineered tissues from chronologically aged MSCs. We compiled unique DNA methylation signatures from chondrogenic, osteogenic, and tenogenic engineered tissues derived from young; n = 4 (21.8 years ± 2.4 SD) and old; n = 4 (65.5 years±8.3SD) human MSCs donors using the Illumina HumanMethylation 450 Beadchip arrays and compared these to gene expression by RNA sequencing. Unique and common signatures of global DNA methylation were identified. There were 201, 67 and 32 chondrogenic, osteogenic and tenogenic age-related DE protein-coding genes respectively. Findings inferred the nature of the transcript networks was predominantly for 'cell death and survival', 'cell morphology', and 'cell growth and proliferation'. Further studies are required to validate if this gene expression effect translates to cell events. Alternative splicing (AS) was dysregulated in ageing with 119, 21 and 9 differential splicing events identified in chondrogenic, osteogenic and tenogenic respectively, and enrichment in genes associated principally with metabolic processes. Gene ontology analysis of differentially methylated loci indicated age-related enrichment for all engineered tissue types in 'skeletal system morphogenesis', 'regulation of cell proliferation' and 'regulation of transcription' suggesting that dynamic epigenetic modifications may occur in genes associated with shared and distinct pathways dependent upon engineered tissue type. An altered phenotype in engineered tissues was observed with ageing at numerous levels. These changes represent novel insights into the ageing process, with implications for stem cell therapies in older patients. In addition we have identified a number of tissue-dependant pathways, which warrant further studies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27533049</pmid><doi>10.1371/journal.pone.0160517</doi><tpages>e0160517</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-08, Vol.11 (8), p.e0160517-e0160517 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1812545672 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Aged Aging - genetics Aging - pathology Alternative Splicing Analysis Arthritis Autografts Biocompatibility Biology and life sciences Biomedical materials Cell death Cell Differentiation Cell morphology Cell Proliferation Cell survival Cells, Cultured Chondrogenesis - genetics Chronic illnesses Connective tissues Cytology Decoding Deoxyribonucleic acid Differentiation DNA DNA Methylation DNA sequencing Engineering and Technology Enrichment Epigenesis, Genetic Epigenetic inheritance Epigenetics Gene expression Gene regulation Gene Regulatory Networks Gene sequencing Genes Genetic aspects Genomes Humans Medicine and Health Sciences Mesenchymal Stem Cells - cytology Mesenchymal Stem Cells - metabolism Mesenchyme Methylation Middle Aged Morphogenesis Musculoskeletal System - metabolism Musculoskeletal System - pathology Oligonucleotide Array Sequence Analysis Osteogenesis - genetics Physiological aspects Regenerative Medicine Ribonucleic acid RNA RNA sequencing Sequence Analysis, RNA Signatures Skeletal system Stem cells Studies Tendons - cytology Tendons - metabolism Tissue engineering Tissue Engineering - methods Transcription Young Adult |
| title | Decoding the Regulatory Landscape of Ageing in Musculoskeletal Engineered Tissues Using Genome-Wide DNA Methylation and RNASeq |
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