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MIR146A inhibits JMJD3 expression and osteogenic differentiation in human mesenchymal stem cells
Jessica M Huszar1, Christopher J Payne1
1Driskill Graduate Program, Departments of Pediatrics and Obstetrics & Gynecology, Northwestern University Feinberg School of Medicine, and Human Molecular Genetics Program, Ann & Robert H. Lurie Children's Hospital of Chicago Research Center, Chicago, IL 60611, USA.
Abstract:
Chromatin remodeling is important for cell differentiation. Histone methyltransferase EZH2 and histone demethylase JMJD3 (KDM6B) modulate levels of histone H3 lysine 27 trimethylation (H3K27me3). Interplay between the two modulators influence lineage specification in stem cells. Here, we identified microRNA MIR146A to be a negative regulator of JMJD3. In the osteogenic differentiation of human mesenchymal stem cells (hMSCs), we observed an upregulation of JMJD3 and a downregulation of MIR146A. Blocking JMJD3 activity in differentiating hMSCs reduced transcript levels of osteogenic gene RUNX2. H3K27me3 levels decreased at the RUNX2 promoter during cell differentiation. Modulation of MIR146A levels in hMSCs altered JMJD3 and RUNX2 expression and affected osteogenic differentiation. We conclude that JMJD3 promotes osteogenesis in differentiating hMSCs, with MIR146A regulating JMJD3.
Insights
MicroRNA 146A (MIR146A) negatively regulates JMJD3, a histone demethylase crucial for osteogenic differentiation in human mesenchymal stem cells (hMSCs). MIR146A modulation impacts JMJD3 and RUNX2 expression, influencing bone cell development.
Area of Science:
- Epigenetics and Gene Regulation
- Stem Cell Biology
- Molecular Endocrinology
Background:
- Chromatin remodeling is essential for cell differentiation processes.
- Histone methyltransferases (e.g., EZH2) and demethylases (e.g., JMJD3/KDM6B) control histone H3 lysine 27 trimethylation (H3K27me3) levels.
- The interplay between these epigenetic modifiers dictates lineage specification in stem cells.
Purpose of the Study:
- To investigate the role of microRNA MIR146A as a regulator of JMJD3.
- To elucidate the function of JMJD3 and MIR146A in the osteogenic differentiation of human mesenchymal stem cells (hMSCs).
- To understand the epigenetic mechanisms involving H3K27me3 modulation at the RUNX2 promoter during osteogenesis.
Main Methods:
- Identification of microRNA MIR146A as a negative regulator of JMJD3.
- Analysis of JMJD3 and MIR146A expression during osteogenic differentiation of hMSCs.
- Pharmacological inhibition of JMJD3 activity and assessment of osteogenic gene (RUNX2) expression and H3K27me3 levels at the RUNX2 promoter.
- Modulation of MIR146A levels in hMSCs to evaluate effects on JMJD3, RUNX2, and osteogenic differentiation.
Main Results:
- During osteogenic differentiation of hMSCs, JMJD3 expression was upregulated, while MIR146A expression was downregulated.
- Inhibition of JMJD3 activity in differentiating hMSCs led to reduced RUNX2 transcript levels.
- H3K27me3 levels decreased at the RUNX2 promoter during hMSC osteogenic differentiation.
- Altering MIR146A levels in hMSCs affected JMJD3 and RUNX2 expression, consequently impacting osteogenic differentiation.
Conclusions:
- JMJD3 plays a critical role in promoting osteogenesis in differentiating hMSCs.
- MIR146A acts as a negative regulator of JMJD3 activity.
- The MIR146A-JMJD3 axis is a key regulatory mechanism in hMSC osteogenic differentiation.
