Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination

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

doi:10.1186/s13072-018-0247-4

Cited by 63 publications

(74 citation statements)

References 56 publications

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“…(71) Future work will be needed to test whether such a rewiring occurs in chondrogenesis, as well upon genetic loss of TET1. TET2 and TET3 have already been shown to be important in adult mesenchymal stem cell (MSC) differentiation (72)(73)(74) ; however, their unique contributions vis-à-vis TET1 remain to be explored. Additionally, in the KD of Tet1, we observed that 72% of differentially expressed genes were upregulated.…”

Section: Discussionmentioning

confidence: 99%

TET1 Directs Chondrogenic Differentiation by Regulating SOX9 Dependent Activation of Col2a1 and Acan In Vitro

et al. 2020

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Skeletal development is a tightly orchestrated process in which cartilage and bone differentiation are intricately intertwined. Recent studies have highlighted the contribution of epigenetic modifications and their writers to skeletal development. Methylated cytosine (5mC) can be oxidized to 5‐hydroxymethylcytosine (5hmC) by the Ten‐eleven‐translocation (TET) enzymes leading to demethylation. We have previously demonstrated that 5hmC is stably accumulated on lineage‐specific genes that are activated during in vitro chondrogenesis in the ATDC5 chondroprogenitors. Knockdown (KD) of Tet1 via short‐hairpin RNAs blocked ATDC5 chondrogenic differentiation. Here, we aimed to provide the mechanistic basis for TET1 function during ATDC5 differentiation. Transcriptomic analysis of Tet1 KD cells demonstrated that 54% of downregulated genes were SOX9 targets, suggesting a role for TET1 in mediating activation of a subset of the SOX9 target genes. Using genome‐wide mapping of 5hmC during ATDC5 differentiation, we found that 5hmC is preferentially accumulated at chondrocyte‐specific class II binding sites for SOX9, as compared with the tissue‐agnostic class I sites. Specifically, we find that SOX9 is unable to bind to Col2a1 and Acan after Tet1 KD, despite no changes in SOX9 levels. Finally, we compared this KD scenario with the genetic loss of TET1 in the growth plate using Tet1−/− embryos, which are approximately 10% smaller than their WT counterparts. In E17.5 Tet1−/− embryos, loss of SOX9 target gene expression is more modest than upon Tet1 KD in vitro. Overall, our data suggest a role for TET1‐mediated 5hmC deposition in partly shaping an epigenome conducive for SOX9 function. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

TET1 Directs Chondrogenic Differentiation by Regulating SOX9 Dependent Activation of Col2a1 and Acan In Vitro

et al. 2020

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“…Yet, there is a lack of information about DNA methylation-based mechanisms that may contribute to MM progression and subsequent bone defects. DNA methylation is an essential epigenetic modification involving the addition of a methyl group to the 5-carbon of the cytosine ring by a family of DNA methyltransferase (DNMT) enzymes 21 , which has been described to play a critical role in MSC lineage determination 22 , as well as in tumor progression and immunosuppression in other cancer types 23 ..…”

Section: Introductionmentioning

confidence: 99%

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

García-Gómez

Rodríguez-Ubreva

et al. 2019

Preprint

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and agarciag@carrerasresearch.org Running title: Reverting DNA methylation to treat MM bone disease Abbreviations: mesenchymal stromal cells, osteoblast, multiple myeloma, DNA methylation Abstract word count: 212 Word count: 3999 Figure count: 5 Reference count: 60 ABSTRACT Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on the bone marrow (BM) microenvironment, in particular on mesenchymal stromal cells (MSCs). MSCs from MM patients exhibit an abnormal transcriptional profile, suggesting that epigenetic alterations could be governing the tumor-promoting functions of MSCs and their prolonged osteoblast (OB) suppression in MM. In this study, we analyzed the DNA methylome of BM-derived MSCs from patients with monoclonal gammopathy of undetermined significance, smoldering myeloma and symptomatic MM at diagnosis in comparison with their normal counterparts. DNA methylation alterations were found at each of the myeloma stage in association with deregulated expression levels of Homeobox genes involved in osteogenic differentiation. Moreover, these DNA methylation changes were recapitulated in vitro by exposing MSCs from healthy individuals to MM plasma cells. Pharmacological targeting of DNMTs and G9a with the dual inhibitor CM-272, reverted the expression of aberrantly methylated osteogenic regulators and promoted OB differentiation of MSCs from myeloma patients. Most importantly, in a mouse model of bone marrow-disseminated MM, administration of CM-272 prevented tumor-associated bone loss and reduced tumor burden. Our results demonstrated that not only was aberrant DNA methylation a main contributor to bone formation impairment found in MM patients, but also its targeting by CM-272 was able to reverse MM-associated bone loss.

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“…The exact reasons for the SETD4 KO-attenuated differentiation potentials were not clear. Change in genomic methylation status may alter the activity of differentiation linage-determined transcription factors [25][26][27], which may help in elucidating this phenotype. We take cardiomyocyte differentiation factors Nkx2.5 and Gata4 as a sample for discussion below.…”

Section: Discussionmentioning

confidence: 99%

SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

Liao

Shao

et al. 2020

Preprint

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Background: Epigenetic modification is a crucial mechanism affecting the biological function of stem cells. SETD4 is a histone methyltransferase, and its biological role in bone marrow mesenchymal stem cells (BMSCs) is currently unknown. This work was aimed to reveal the SETD4 biological role as well as its impacts on the genomic methylation profiles in BMSCs. Methods: BMSCs were isolated form SETD4 knockout (KO) and wild type (WT) mice that established by CRISPR/Cas9 technology. The cell proliferation, migration, myogenic differentiation and angiogenesis were tested according to appropriate biology techniques. And the Reduced Representation Bisulfite Sequencing (RRBS) method was adopted to analyze the global genomic methylation profiles of BMSCs, following bioinformatics analysis of GO functions and KEGG signaling of differential methylated CpG sites and differential methylation regions (DMRs). Finally, validation experiments were conducted to examine the expression of histone lysine methyltransferase and some representative genes. Results: SETD4 KO significantly promoted BMSCs proliferation, which was characterized by enhanced cell viability and increased expression of PCNA, Cyclin A2, Cyclin E1, CDK2, CDK6, Bcl2 and decreased the expression of P16, P21 and Caspase3. SETD4 deficiency impaired BMSCs migration and myogenic differentiation potentials, and even the angiogenesis via paracrine of VEGF. Compared with WT control, the overall genomic methylation of BMSCs in the SETD4 KO group only was decreased by 0.47%. However, the changed genomic methylation covers a total of 96,331 differential methylated CpG sites and 8692 DMR, with part of them settled in promoter regions. GO and KEGG analysis revealed that differential CpG islands and DMRs in promotes impacted 270 GO functions and 34 KEGG signaling pathways, with some closely related to stem cell biology. SETD4 KO inhibited sets of monomethylases and dimethylases for histone lysine, along with significant changes in some factors including Nkx2.5, Gata4, Gli2, Grem2, E2f7, Map7, Nr2f2 and Shox2 that associated with stem cell biology. Conclusions: These results are the first to reveal that even though SETD4 changes the genome’s overall methylation to a limited extent in BMSCs, it still affects the numerous cellular functions and signaling pathways, implying SETD4-altered genomic methylation serves a crucial molecular role in BMSCs’ biological functions.

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Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination

Cited by 63 publications

References 56 publications

TET1 Directs Chondrogenic Differentiation by Regulating SOX9 Dependent Activation of Col2a1 and Acan In Vitro

TET1 Directs Chondrogenic Differentiation by Regulating SOX9 Dependent Activation of Col2a1 and Acan In Vitro

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

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