Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/121909
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Type: Journal article
Title: Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination
Author: Cakouros, D.
Hemming, S.
Gronthos, K.
Liu, R.
Zannettino, A.
Shi, S.
Gronthos, S.
Citation: Epigenetics and Chromatin, 2019; 12(1):20
Publisher: BMC
Issue Date: 2019
ISSN: 1756-8935
1756-8935
Statement of
Responsibility: 
Dimitrios Cakouros, Sarah Hemming, Kahlia Gronthos, Renjing Liu, Andrew Zannettino, Songtao Shi and Stan Gronthos
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
Rights: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
RMID: 0030106525
DOI: 10.1186/s13072-018-0247-4
Grant ID: http://purl.org/au-research/grants/nhmrc/1141361
http://purl.org/au-research/grants/nhmrc/1042677
Appears in Collections:Medicine publications

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