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.
| Language | English |
|---|---|
| Article number | 0247 |
| Journal | Epigenetics and Chromatin |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| State | Published - 3 Jan 2019 |
Keywords
- Epigenetics
- Hydroxymethylation
- Mesenchymal stem cells
- Osteogenesis
- Osteoporosis
- TET
ASJC Scopus subject areas
- Molecular Biology
- Genetics
Cite this
}
Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination 06 Biological Sciences 0601 Biochemistry and Cell Biology 06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1103 Clinical Sciences. / Cakouros, Dimitrios; Hemming, Sarah; Gronthos, Kahlia; Liu, Renjing; Zannettino, Andrew; Shi, Songtao; Gronthos, Stan.
In: Epigenetics and Chromatin, Vol. 12, No. 1, 0247, 03.01.2019.Research output: Research - peer-review › Article
TY - JOUR
T1 - Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination 06 Biological Sciences 0601 Biochemistry and Cell Biology 06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1103 Clinical Sciences
AU - Cakouros,Dimitrios
AU - Hemming,Sarah
AU - Gronthos,Kahlia
AU - Liu,Renjing
AU - Zannettino,Andrew
AU - Shi,Songtao
AU - Gronthos,Stan
PY - 2019/1/3
Y1 - 2019/1/3
N2 - 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.
AB - 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.
KW - Epigenetics
KW - Hydroxymethylation
KW - Mesenchymal stem cells
KW - Osteogenesis
KW - Osteoporosis
KW - TET
UR - http://www.scopus.com/inward/record.url?scp=85059497455&partnerID=8YFLogxK
U2 - 10.1186/s13072-018-0247-4
DO - 10.1186/s13072-018-0247-4
M3 - Article
VL - 12
JO - Epigenetics and Chromatin
T2 - Epigenetics and Chromatin
JF - Epigenetics and Chromatin
SN - 1756-8935
IS - 1
M1 - 0247
ER -