H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells
During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SET...
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| description | During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis. |
| doi_str_mv | 10.1371/journal.pbio.2006522 |
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Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.2006522</identifier><identifier>PMID: 30422989</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adipocytes ; Adipogenesis ; Adipose tissue ; Aging ; Biochemistry ; Biocompatibility ; Bioinformatics ; Biology ; Biology and Life Sciences ; Biomedical materials ; Bone diseases ; Bone loss ; Bone marrow ; Cell fate ; Chromatin ; Clonal deletion ; Elongation ; Epigenetics ; Funding ; Gene expression ; Gene sequencing ; Histone methyltransferase ; Immunoprecipitation ; Laboratories ; Lipopolysaccharide-binding protein ; Lipopolysaccharides ; Lysine ; Medical research ; Medical treatment ; Medicine and Health Sciences ; Mesenchymal stem cells ; Mesenchyme ; Methylation ; Observations ; Osteoblastogenesis ; Osteoblasts ; Osteogenesis ; Osteoporosis ; Phosphotransferases ; Physiological aspects ; Proteins ; Ribonucleic acid ; RNA ; Stem cell transplantation ; Stem cells ; Target recognition ; Transcription elongation</subject><ispartof>PLoS biology, 2018-11, Vol.16 (11), p.e2006522-e2006522</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Wang 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>2018 Wang et al 2018 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c761t-a90124f97a9f5411db293d773304f354489f042163cbc7ff91f811835103d6383</citedby><cites>FETCH-LOGICAL-c761t-a90124f97a9f5411db293d773304f354489f042163cbc7ff91f811835103d6383</cites><orcidid>0000-0002-3686-6098</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233919/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233919/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30422989$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Lijun</creatorcontrib><creatorcontrib>Niu, Ningning</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Shao, Rui</creatorcontrib><creatorcontrib>Ouyang, Huiling</creatorcontrib><creatorcontrib>Zou, Weiguo</creatorcontrib><title>H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells</title><title>PLoS biology</title><addtitle>PLoS Biol</addtitle><description>During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis.</description><subject>Adipocytes</subject><subject>Adipogenesis</subject><subject>Adipose tissue</subject><subject>Aging</subject><subject>Biochemistry</subject><subject>Biocompatibility</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Biomedical materials</subject><subject>Bone diseases</subject><subject>Bone loss</subject><subject>Bone marrow</subject><subject>Cell fate</subject><subject>Chromatin</subject><subject>Clonal deletion</subject><subject>Elongation</subject><subject>Epigenetics</subject><subject>Funding</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Histone methyltransferase</subject><subject>Immunoprecipitation</subject><subject>Laboratories</subject><subject>Lipopolysaccharide-binding protein</subject><subject>Lipopolysaccharides</subject><subject>Lysine</subject><subject>Medical research</subject><subject>Medical treatment</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchyme</subject><subject>Methylation</subject><subject>Observations</subject><subject>Osteoblastogenesis</subject><subject>Osteoblasts</subject><subject>Osteogenesis</subject><subject>Osteoporosis</subject><subject>Phosphotransferases</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Target recognition</subject><subject>Transcription 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trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells</title><author>Wang, Lijun ; Niu, Ningning ; Li, Li ; Shao, Rui ; Ouyang, Huiling ; Zou, Weiguo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c761t-a90124f97a9f5411db293d773304f354489f042163cbc7ff91f811835103d6383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adipocytes</topic><topic>Adipogenesis</topic><topic>Adipose tissue</topic><topic>Aging</topic><topic>Biochemistry</topic><topic>Biocompatibility</topic><topic>Bioinformatics</topic><topic>Biology</topic><topic>Biology and Life Sciences</topic><topic>Biomedical materials</topic><topic>Bone diseases</topic><topic>Bone loss</topic><topic>Bone marrow</topic><topic>Cell fate</topic><topic>Chromatin</topic><topic>Clonal deletion</topic><topic>Elongation</topic><topic>Epigenetics</topic><topic>Funding</topic><topic>Gene expression</topic><topic>Gene sequencing</topic><topic>Histone methyltransferase</topic><topic>Immunoprecipitation</topic><topic>Laboratories</topic><topic>Lipopolysaccharide-binding protein</topic><topic>Lipopolysaccharides</topic><topic>Lysine</topic><topic>Medical research</topic><topic>Medical treatment</topic><topic>Medicine and Health Sciences</topic><topic>Mesenchymal stem cells</topic><topic>Mesenchyme</topic><topic>Methylation</topic><topic>Observations</topic><topic>Osteoblastogenesis</topic><topic>Osteoblasts</topic><topic>Osteogenesis</topic><topic>Osteoporosis</topic><topic>Phosphotransferases</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Target recognition</topic><topic>Transcription elongation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Lijun</creatorcontrib><creatorcontrib>Niu, Ningning</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Shao, Rui</creatorcontrib><creatorcontrib>Ouyang, Huiling</creatorcontrib><creatorcontrib>Zou, Weiguo</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 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Biol</addtitle><date>2018-11-13</date><risdate>2018</risdate><volume>16</volume><issue>11</issue><spage>e2006522</spage><epage>e2006522</epage><pages>e2006522-e2006522</pages><issn>1545-7885</issn><issn>1544-9173</issn><eissn>1545-7885</eissn><abstract>During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30422989</pmid><doi>10.1371/journal.pbio.2006522</doi><orcidid>https://orcid.org/0000-0002-3686-6098</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adipocytes Adipogenesis Adipose tissue Aging Biochemistry Biocompatibility Bioinformatics Biology Biology and Life Sciences Biomedical materials Bone diseases Bone loss Bone marrow Cell fate Chromatin Clonal deletion Elongation Epigenetics Funding Gene expression Gene sequencing Histone methyltransferase Immunoprecipitation Laboratories Lipopolysaccharide-binding protein Lipopolysaccharides Lysine Medical research Medical treatment Medicine and Health Sciences Mesenchymal stem cells Mesenchyme Methylation Observations Osteoblastogenesis Osteoblasts Osteogenesis Osteoporosis Phosphotransferases Physiological aspects Proteins Ribonucleic acid RNA Stem cell transplantation Stem cells Target recognition Transcription elongation |
| title | H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells |
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