Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

Dudakovic, Amel; Camilleri, Emily T.; Xu, Fusheng; Riester, Scott M.; McGee‐Lawrence, Meghan E.; Bradley, Elizabeth W.; Paradise, Christopher R.; Lewallen, Eric A.; Thaler, Roman; Deyle, David R.; Larson, A. Noelle; Lewallen, David G.; Dietz, Allan B.; Stein, Gary S.; Montecino, Martín; Westendorf, Jennifer J.; Wijnen, André J. van

doi:10.1074/jbc.m115.672345

Cited by 150 publications

(210 citation statements)

References 66 publications

(67 reference statements)

Supporting

Mentioning

180

Contrasting

Order By: Relevance

“…Although the Runx2 P1 promoter or the Sp7 promoter are not CpG methylation-sensitive by SFN treatment, we measured a significant increase in 5hmC levels in the Atf4 promoter with a concomitant increase in Atf4 gene expression, demonstrating a mechanistic link between active DNA demethylation and enhanced osteoblastic differentiation. Interestingly, as we have shown before, early modulation of epigenetic marks like inhibition of histone acetylation or methylation (69,70) and, as shown here, an increase of active DNA demethylation show long term effects on osteoblastic differentiation, suggesting that SFN may specifi- cally support epigenetic chromatin reprogramming at early differentiation stages.…”

Section: Discussionsupporting

confidence: 82%

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Thaler

Maurizi

Roschger

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation via Tet1 and Tet2 and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2, Col1a1, Bglap2, Sp7, Atf4, and Alpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-B ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of the Tet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (ϳ20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorption in vivo. Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.

show abstract

Section: Discussionsupporting

confidence: 82%

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Thaler

Maurizi

Roschger

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Conditional genetic loss of Ezh2 in uncommitted mouse mesenchymal cells results in multiple defects in skeletal patterning and bone formation (85). Extensive transcriptomic analyses revealed that Ezh2-null cells exhibit elevated levels of Runx2 mRNA expression, consistent with accelerated cessation of cell growth and precocious maturation of osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Polycomb PRC2 complex mediates epigenetic silencing of a critical osteogenic master regulator in the hippocampus

Aguilar

Bustos

Sáez

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

Self Cite

View full text Add to dashboard Cite

During hippocampal neuron differentiation, the expression of critical inducers of non-neuronal cell lineages must be efficiently silenced. Runx2 transcription factor is the master regulator of mesenchymal cells responsible for intramembranous osteoblast differentiation and formation of the craniofacial bone tissue that surrounds and protects the central nervous system (CNS) in mammalian embryos. The molecular mechanisms that mediate silencing of the Runx2 gene and its downstream target osteogenic-related genes in neuronal cells have not been explored. Here, we assess the epigenetic mechanisms that mediate silencing of osteoblast-specific genes in CNS neurons. In particular, we address the contribution of histone epigenetic marks and histone modifiers on the silencing of the Runx2/p57 bone-related isoform in rat hippocampal tissues at embryonic to adult stages. Our results indicate enrichment of repressive chromatin histone marks and of the Polycomb PRC2 complex at the Runx2/p57 promoter region. Knockdown of PRC2 H3K27-methyltransferases Ezh2 and Ezh1, or forced expression of the Trithorax/COMPASS subunit Wdr5 activates Runx2/p57 mRNA expression in both immature and mature hippocampal cells. Together these results indicate that complementary epigenetic mechanisms progressively and efficiently silence critical osteoblastic genes during hippocampal neuron differentiation.

show abstract

“…We also show that when AMSCs differentiate on ps-Ti, they produce high levels of mRNAs for bone-related collagenous and non-collagenous proteins (e.g., collagens and proteoglycans), as well as paracrine signaling ligands (e.g., cytokines and chemokines). Recent data from our group indicate that these bone-anabolic functions of AMSCs can be enhanced by inhibiting epigenetic enzymes [36]. Thus, it is feasible to design strategies to test the role of specific epigenetic inhibitors on expression of bone-related ECM proteins during osteogenic differentiation of AMSCs on ps-Ti in three-dimensional culture.…”

Section: Discussionmentioning

confidence: 99%

Osteogenic potential of human adipose-tissue-derived mesenchymal stromal cells cultured on 3D-printed porous structured titanium

Lewallen

Jones

Dudakovic

et al. 2016

Gene

Self Cite

View full text Add to dashboard Cite

Integration of porous metal prosthetics, which restore form and function of irreversibly damaged joints, into remaining healthy bone is critical for implant success. We investigated the biological properties of adipose-tissue derived mesenchymal stromal/stem cells (AMSCs) and addressed their potential to alter the in vitro microenvironment of implants. We employed human AMSCs as a practical source for musculoskeletal applications, because these cells can be obtained in large quantities, are multipotent, and have trophic paracrine functions. AMSCs were cultured on surgical-grade porous titanium discs as a model for orthopedic implants. We monitored cell/substrate attachment, cell proliferation, multipotency, and differentiation phenotypes of AMSCs upon osteogenic induction. High-resolution scanning electron microscopy and histology revealed that AMSCs adhere to the porous metallic surface. Compared to standard tissue culture plastic, AMSCs grown in the porous titanium microenvironment showed differences in temporal expression for genes involved in cell cycle progression (CCNB2, HIST2H4), extracellular matrix production (COL1A1, COL3A1), mesenchymal lineage identity (ACTA2, CD248, CD44), osteoblastic transcription factors (DLX3, DLX5, ID3) and epigenetic regulators (EZH1, EZH2). We conclude that metal orthopedic implants can be effectively seeded with clinical-grade stem/stromal cells to create a pre-conditioned implant.

show abstract

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

Cited by 150 publications

References 66 publications

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Polycomb PRC2 complex mediates epigenetic silencing of a critical osteogenic master regulator in the hippocampus

Osteogenic potential of human adipose-tissue-derived mesenchymal stromal cells cultured on 3D-printed porous structured titanium

Contact Info

Product

Resources

About