Related Experiment Video

Updated: Mar 21, 2026

In Vitro Selection of Engineered Transcriptional Repressors for Targeted Epigenetic Silencing
10:44

In Vitro Selection of Engineered Transcriptional Repressors for Targeted Epigenetic Silencing

Published on: May 5, 2023

2.0K

Cutting Edge: EZH2 Promotes Osteoclastogenesis by Epigenetic Silencing of the Negative Regulator IRF8

Celestia Fang1, Yu Qiao1, Se Hwan Mun1

  • 1Arthritis and Tissue Degeneration Program David Z. Rosensweig Genomics Research Center Hospital for Special Surgery.

Journal of Immunology (Baltimore, Md. : 1950)
|May 17, 2016
PubMed

Insights

Epigenetic regulator EZH2 silences the negative osteoclast regulator IRF8 via histone methylation, impacting bone remodeling. EZH2 inhibition reduced bone loss in an osteoporosis model.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Bone Biology

Background:

  • Osteoclasts are crucial for bone remodeling and resorption.
  • Epigenetic mechanisms, including DNA methylation, regulate osteoclast differentiation.
  • Irf8 (interferon regulatory factor 8) acts as a negative regulator of osteoclastogenesis.

Purpose of the Study:

  • To investigate the role of EZH2 (Enhancer of Zeste Homolog 2) in osteoclastogenesis.
  • To elucidate the epigenetic mechanism by which EZH2 regulates IRF8 expression.
  • To evaluate the therapeutic potential of EZH2 inhibition in osteoporosis.

Main Methods:

  • Inhibition of EZH2 using the small molecule GSK126.
  • Decreased EZH2 expression via antisense oligonucleotides.
  • Analysis of EZH2 recruitment to the IRF8 promoter and H3K27me3 deposition.
  • Assessment of osteoclast differentiation in vitro.
  • Evaluation of bone loss in an ovariectomy-induced osteoporosis mouse model.

Main Results:

  • Inhibition or knockdown of EZH2 impaired osteoclast differentiation.
  • EZH2 was recruited to the IRF8 promoter following RANKL stimulation, leading to H3K27me3 deposition and IRF8 downregulation.
  • GSK126 treatment attenuated bone loss in the ovariectomy mouse model.

Conclusions:

  • EZH2 epigenetically silences IRF8 expression through histone methylation during osteoclastogenesis.
  • This mechanism complements DNA methylation in regulating IRF8.
  • EZH2 inhibition represents a potential therapeutic strategy for osteoporosis by targeting IRF8-mediated osteoclast regulation.

More Related Videos

In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells10:26

In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells

Published on: January 20, 2019

13.3K
A Simple Pit Assay Protocol to Visualize and Quantify Osteoclastic Resorption In Vitro07:03

A Simple Pit Assay Protocol to Visualize and Quantify Osteoclastic Resorption In Vitro

Published on: June 16, 2022

7.6K

Related Concept Videos

Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
4.1K
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
34.2K
Epigenetic Regulation01:46

Epigenetic Regulation

26.2K
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
3.9K
Osteoclasts in Bone Remodeling01:31

Osteoclasts in Bone Remodeling

Osteoclasts are cells responsible for bone resorption and remodeling. They originate from hematopoietic progenitor cells present in the bone marrow. Numerous progenitor cells fuse to form multinucleated cells, each with 10-20 nuclei. A single osteoclast has a diameter of 150 to 200 µM. These cells have ruffled borders that break down the underlying bone tissue and release minerals such as calcium into the blood in bone resorption. Osteoclasts cling to bones with their ruffled edges during...
4.6K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
3.0K