The Role of <i>Dot1l</i> in Prenatal and Postnatal Murine Chondrocytes and Trabecular Bone

Jo, Stephanie Y.; Domowicz, Miriam S.; Henry, Judith; Schwartz, Nancy B.

doi:10.1002/jbm4.10254

Cited by 12 publications

(6 citation statements)

References 41 publications

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“…Activation of Wnt signaling is suggested to stimulate chondrocyte hypertrophy and inhibit chondrogenesis, which has been considered as a risk factor for OA (Usami et al, 2016). These findings are consistent with what is observed in mice with deletion of Dot1l in chondrocytes, characterized by reduction in proteoglycan component of the ECM (e.g., chondroitin sulfate), decreased chondrocyte proliferation and accelerated OA progression (Cornelis et al, 2019;Jo et al, 2020). Mice lacking Dot1l in mesenchymal progenitors exhibit skeletal dysplasia characterized by limb shortening, abnormal bone morphologies and forelimb dislocations (Sutter et al, 2021).…”

Section: Histone Methyltransferases (Hmts)supporting

confidence: 76%

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

Wan

Zhang

Yao

et al. 2021

Front. Cell Dev. Biol.

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The involvement of histone modifications in cartilage development, pathology and regeneration is becoming increasingly evident. Understanding the molecular mechanisms and consequences of histone modification enzymes in cartilage development, homeostasis and pathology provides fundamental and precise perspectives to interpret the biological behavior of chondrocytes during skeletal development and the pathogenesis of various cartilage related diseases. Candidate molecules or drugs that target histone modifying proteins have shown promising therapeutic potential in the treatment of cartilage lesions associated with joint degeneration and other chondropathies. In this review, we summarized the advances in the understanding of histone modifications in the regulation of chondrocyte fate, cartilage development and pathology, particularly the molecular writers, erasers and readers involved. In addition, we have highlighted recent studies on the use of small molecules and drugs to manipulate histone signals to regulate chondrocyte functions or treat cartilage lesions, in particular osteoarthritis (OA), and discussed their potential therapeutic benefits and limitations in preventing articular cartilage degeneration or promoting its repair or regeneration.

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Section: Histone Methyltransferases (Hmts)supporting

confidence: 76%

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

Wan

Zhang

Yao

et al. 2021

Front. Cell Dev. Biol.

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“…Lineage-specific DOT1L-KO during mouse development has recently been explored in numerous tissues with various CRE drivers ( Table 2 ) (Summarized in Figure 6 ). DOT1L-KO in cardiac tissue ( Nguyen et al, 2011 ), cerebral cortex ( Franz et al, 2019 ), endothelium ( Yoo et al, 2020 ), and cartilage ( Jo et al, 2020 ) results in perinatal lethality. DOT1L-KO in the cerebellum does not affect viability but does disrupt tissue organization and cause motor defects ( Bovio et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Connecting the DOTs on Cell Identity

Wille

Sridharan

2022

Front. Cell Dev. Biol.

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DOT1-Like (DOT1L) is the sole methyltransferase of histone H3K79, a modification enriched mainly on the bodies of actively transcribing genes. DOT1L has been extensively studied in leukemia were some of the most frequent onco-fusion proteins contain portions of DOT1L associated factors that mislocalize H3K79 methylation and drive oncogenesis. However, the role of DOT1L in non-transformed, developmental contexts is less clear. Here we assess the known functional roles of DOT1L both in vitro cell culture and in vivo models of mammalian development. DOT1L is evicted during the 2-cell stage when cells are totipotent and massive epigenetic and transcriptional alterations occur. Embryonic stem cell lines that are derived from the blastocyst tolerate the loss of DOT1L, while the reduction of DOT1L protein levels or its catalytic activity greatly enhances somatic cell reprogramming to induced pluripotent stem cells. DOT1L knockout mice are embryonically lethal when organogenesis commences. We catalog the rapidly increasing studies of total and lineage specific knockout model systems that show that DOT1L is broadly required for differentiation. Reduced DOT1L activity is concomitant with increased developmental potential. Contrary to what would be expected of a modification that is associated with active transcription, loss of DOT1L activity results in more upregulated than downregulated genes. DOT1L also participates in various epigenetic networks that are both cell type and developmental stage specific. Taken together, the functions of DOT1L during development are pleiotropic and involve gene regulation at the locus specific and global levels.

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“…For investigation of bone metabolism, different promoters that drive osteogenic gene expression in bone, combined with the Cre‐loxP system, have been used to study the roles of bone‐specific genes during bone development including Col1, ( 27 ) Col2, ( 28–30 ) Osx, (31 ) and Prrx1, which is specifically expressed in MSC which drive long‐bone osteoblast formation ( 10 ) and which we utilized in our experiments. An inducible Cre system activated by cell‐specific regulatory elements such as the estrogen receptor (ER) further allows temporal induction through the use of exogenous inducers such as TAM, and has become a broadly applied technique.…”

Section: Discussionmentioning

confidence: 99%

Low‐Dose Tamoxifen Induces Significant Bone Formation in Mice

et al. 2021

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Use of the selective estrogen receptor modulator Tamoxifen (TAM) is a mainstay to induce conditional expression of Cre recombinase in transgenic laboratory mice. To excise β-catenin fl/fl in 28-day-old male and female Prrx1-CreER/β-catenin fl/fl mice (C57BL/6), we utilized TAM at 150 mg/kg; despite β-catenin knockout in MSC, we found a significant increase in trabecular and cortical bone volume in all genders. Because TAM was similarly anabolic in KO and control mice, we investigated a dose effect on bone formation by treating wild-type mice (WT C57BL/6, 4 weeks) with TAM (total dose 0, 20, 40, 200 mg/kg via four injections). TAM increased bone in a dosedependent manner analyzed by micro-computed tomography (μCT), which showed that, compared to control, 20 mg/kg TAM increased femoral bone volume fraction (bone volume/total volume [BV/TV]) (21.6% ± 1.5% to 33% ± 2.5%; 153%, p < 0.005). With TAM 40 mg/kg and 200 mg/kg, BV/TV increased to 48.1% ± 4.4% (223%, p < 0.0005) and 58% ± 3.8% (269%, p < 0.0001) respectively, compared to control. Osteoblast markers increased with 200 mg/kg TAM: Dlx5 (224%, p < 0.0001), Alp (166%, p < 0.0001), Bglap (223%, p < 0.0001), and Sp7 (228%, p < 0.0001). Osteoclasts per bone surface (Oc#/BS) nearly doubled at the lowest TAM dose (20 mg/kg), but decreased to <20% control with 200 mg/kg TAM. Our data establish that use of TAM at even very low doses to excise a floxed target in postnatal mice has profound effects on trabecular and cortical bone formation. As such, TAM treatment is a major confounder in the interpretation of bone phenotypes in conditional gene knockout mouse models.

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The Role of Dot1l in Prenatal and Postnatal Murine Chondrocytes and Trabecular Bone

Cited by 12 publications

References 41 publications

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

Connecting the DOTs on Cell Identity

Low‐Dose Tamoxifen Induces Significant Bone Formation in Mice

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