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A Two-Step Strategy that Combines Epigenetic Modification and Biomechanical Cues to Generate Mammalian Pluripotent Cells
Published on: August 29, 2020
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Ezh2 mediated H3K27me3 activity facilitates somatic transition during human pluripotent reprogramming
Radhika Arasala Rao1, Narendra Dhele2, Sabna Cheemadan3
11] Centre For Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology and Regenerative Medicine (inStem), National Centre for Biological Sciences, GKVK Campus, Bellary Road, Bangalore 560065, Karnataka, India [2] Sastra University, Tirumalaisamudram, Thanjavur - 613 401, TamilNadu, India.
Scientific Reports
|February 5, 2015
Summary
Enhancer of Zeste homolog 2 (Ezh2) is crucial for mesenchymal to epithelial transition (MET) during human induced pluripotent stem cell (iPSC) generation. Its histone methyltransferase activity and association with c-Myc regulate TGF-β signaling and microRNAs, facilitating pluripotency induction.
Area of Science:
- Epigenetics and Stem Cell Biology
- Cellular Reprogramming Mechanisms
- Chromatin Regulation in Development
Background:
- Cellular reprogramming to induced pluripotent stem cells (iPSC) involves significant epigenetic changes.
- Chromatin regulators like Ezh2 play a role in establishing pluripotency.
- The precise mechanisms linking transcription factors and chromatin modulators in reprogramming are not fully understood.
Purpose of the Study:
- To investigate the role of Ezh2's histone methyltransferase activity in human iPSC generation.
- To elucidate the molecular mechanisms by which Ezh2 influences mesenchymal to epithelial transition (MET).
- To understand Ezh2's interaction with transcription factors and its impact on gene and microRNA expression during reprogramming.
Main Methods:
- Assessing the requirement of Ezh2's histone methyltransferase activity for MET.
- Analyzing the effect of H3K27 trimethylation (H3K27me3) on pluripotency induction via TGF-β signaling.
- Investigating Ezh2's regulation of pro-epithelial-mesenchymal transition (EMT) microRNAs, including the miR-23a locus.
- Examining the association between Ezh2 and c-Myc in silencing key regulatory pathways.
Main Results:
- Ezh2's histone methyltransferase activity is essential for MET during human iPSC generation.
- H3K27me3, mediated by Ezh2, promotes pluripotency by transcriptionally targeting the TGF-β signaling pathway.
- Ezh2 negatively regulates pro-EMT microRNAs, such as the miR-23a locus, during MET.
- A specific interaction between Ezh2 and c-Myc is necessary for silencing the somatic cell program.
Conclusions:
- Ezh2 restricts the somatic cell program during the early stages of cellular reprogramming.
- Ezh2-dependent H3K27me3 activity is critical for both transcriptional and microRNA modulation in human iPSC generation.
- These findings provide a mechanistic understanding of Ezh2's function in facilitating cellular reprogramming.
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