Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination
Abstract Background The 5 hydroxymethylation (5hmC) mark and TET DNA dioxygenases play a pivotal role in embryonic stem cell differentiation and animal development. However, very little is known about TET enzymes in lineage determination of human bone marrow-derived mesenchymal stem/stromal cells (B...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Epigenetics & Chromatin |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13072-018-0247-4 |
| _version_ | 1818258614886858752 |
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| author | Dimitrios Cakouros Sarah Hemming Kahlia Gronthos Renjing Liu Andrew Zannettino Songtao Shi Stan Gronthos |
| author_facet | Dimitrios Cakouros Sarah Hemming Kahlia Gronthos Renjing Liu Andrew Zannettino Songtao Shi Stan Gronthos |
| author_sort | Dimitrios Cakouros |
| collection | DOAJ |
| description | Abstract Background The 5 hydroxymethylation (5hmC) mark and TET DNA dioxygenases play a pivotal role in embryonic stem cell differentiation and animal development. However, very little is known about TET enzymes in lineage determination of human bone marrow-derived mesenchymal stem/stromal cells (BMSC). We examined the function of all three TET DNA dioxygenases, responsible for DNA hydroxymethylation, in human BMSC cell osteogenic and adipogenic differentiation. Results We used siRNA knockdown and retroviral mediated enforced expression of TET molecules and discovered TET1 to be a repressor of both osteogenesis and adipogenesis. TET1 was found to recruit the co-repressor proteins, SIN3A and the histone lysine methyltransferase, EZH2 to osteogenic genes. Conversely, TET2 was found to be a promoter of both osteogenesis and adipogenesis. The data showed that TET2 was directly responsible for 5hmC levels on osteogenic and adipogenic lineage-associated genes, whereas TET1 also played a role in this process. Interestingly, TET3 showed no functional effect in BMSC osteo-/adipogenic differentiation. Finally, in a mouse model of ovariectomy-induced osteoporosis, the numbers of clonogenic BMSC were dramatically diminished corresponding to lower trabecular bone volume and reduced levels of TET1, TET2 and 5hmC. Conclusion The present study has discovered an epigenetic mechanism mediated through changes in DNA hydroxymethylation status regulating the activation of key genes involved in the lineage determination of skeletal stem cells, which may have implications in BMSC function during normal bone regulation. Targeting TET molecules or their downstream targets may offer new therapeutic strategies to help prevent bone loss and repair following trauma or disease. |
| first_indexed | 2024-12-12T18:02:21Z |
| format | Article |
| id | doaj.art-3a6a75508e6042c89322bdc67e374dcb |
| institution | Directory Open Access Journal |
| issn | 1756-8935 |
| language | English |
| last_indexed | 2024-12-12T18:02:21Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Epigenetics & Chromatin |
| spelling | doaj.art-3a6a75508e6042c89322bdc67e374dcb2022-12-22T00:16:35ZengBMCEpigenetics & Chromatin1756-89352019-01-0112112010.1186/s13072-018-0247-4Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determinationDimitrios Cakouros0Sarah Hemming1Kahlia Gronthos2Renjing Liu3Andrew Zannettino4Songtao Shi5Stan Gronthos6Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of AdelaideMesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of AdelaideMesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of AdelaideAgnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute for Cancer Medicine and Cell Biology, University of SydneySouth Australian Health and Medical Research InstituteDepartment of Anatomy and Cell Biology, School of Dental Medicine, University of PennsylvaniaMesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of AdelaideAbstract Background The 5 hydroxymethylation (5hmC) mark and TET DNA dioxygenases play a pivotal role in embryonic stem cell differentiation and animal development. However, very little is known about TET enzymes in lineage determination of human bone marrow-derived mesenchymal stem/stromal cells (BMSC). We examined the function of all three TET DNA dioxygenases, responsible for DNA hydroxymethylation, in human BMSC cell osteogenic and adipogenic differentiation. Results We used siRNA knockdown and retroviral mediated enforced expression of TET molecules and discovered TET1 to be a repressor of both osteogenesis and adipogenesis. TET1 was found to recruit the co-repressor proteins, SIN3A and the histone lysine methyltransferase, EZH2 to osteogenic genes. Conversely, TET2 was found to be a promoter of both osteogenesis and adipogenesis. The data showed that TET2 was directly responsible for 5hmC levels on osteogenic and adipogenic lineage-associated genes, whereas TET1 also played a role in this process. Interestingly, TET3 showed no functional effect in BMSC osteo-/adipogenic differentiation. Finally, in a mouse model of ovariectomy-induced osteoporosis, the numbers of clonogenic BMSC were dramatically diminished corresponding to lower trabecular bone volume and reduced levels of TET1, TET2 and 5hmC. Conclusion The present study has discovered an epigenetic mechanism mediated through changes in DNA hydroxymethylation status regulating the activation of key genes involved in the lineage determination of skeletal stem cells, which may have implications in BMSC function during normal bone regulation. Targeting TET molecules or their downstream targets may offer new therapeutic strategies to help prevent bone loss and repair following trauma or disease.http://link.springer.com/article/10.1186/s13072-018-0247-4Mesenchymal stem cellsOsteogenesisEpigeneticsHydroxymethylationTETOsteoporosis |
| spellingShingle | Dimitrios Cakouros Sarah Hemming Kahlia Gronthos Renjing Liu Andrew Zannettino Songtao Shi Stan Gronthos Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination Epigenetics & Chromatin Mesenchymal stem cells Osteogenesis Epigenetics Hydroxymethylation TET Osteoporosis |
| title | Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination |
| title_full | Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination |
| title_fullStr | Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination |
| title_full_unstemmed | Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination |
| title_short | Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination |
| title_sort | specific functions of tet1 and tet2 in regulating mesenchymal cell lineage determination |
| topic | Mesenchymal stem cells Osteogenesis Epigenetics Hydroxymethylation TET Osteoporosis |
| url | http://link.springer.com/article/10.1186/s13072-018-0247-4 |
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