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

Dimitrios Cakouros, Sarah Hemming, Kahlia Gronthos, Renjing Liu, Andrew Zannettino, Songtao Shi, Stan Gronthos

Research output: Contribution to journalArticle

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.

LanguageEnglish
Article number0247
JournalEpigenetics and Chromatin
Volume12
Issue number1
DOIs
Publication statusPublished - 3 Jan 2019

Keywords

  • Epigenetics
  • Hydroxymethylation
  • Mesenchymal stem cells
  • Osteogenesis
  • Osteoporosis
  • TET

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

@article{aed9cd860d1942aa966724047f39bbd8,
title = "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",
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.",
keywords = "Epigenetics, Hydroxymethylation, Mesenchymal stem cells, Osteogenesis, Osteoporosis, TET",
author = "Dimitrios Cakouros and Sarah Hemming and Kahlia Gronthos and Renjing Liu and Andrew Zannettino and Songtao Shi and Stan Gronthos",
year = "2019",
month = "1",
day = "3",
doi = "10.1186/s13072-018-0247-4",
language = "English",
volume = "12",
journal = "Epigenetics and Chromatin",
issn = "1756-8935",
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}

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: Contribution to journalArticle

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

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