Abstract
Results Genome-wide analysis of histone modifications documented that adult hCSCs are characterized by a bivalent chromatin configuration similar to that of embryonic stem cells with repressive and activating marks at lysine residues of histones H3 and H4. The high levels of di-(H3K4me2) and tri-methylation (H3K4me3) at lysine 4 of histone H3 prompted us to test the function of histone methyltransferase Smyd3, which is downregulated by the non-functional mutation in the c-kit receptor, in hCSCs. Inhibition of Smyd3 by siRNA strategy decreased the fraction (60%) of cycling hCSCs and increased apoptosis (2.5-fold). Attenuation of hCSC growth was coupled with a decline in the expression of telomerase, hTERT, and the myocyte specific transcription factors hNkx2.5 and hGata6. By immunolabeling, Smyd3 co-localized with hTERT, hNkx2.5 and hGATA6 in hCSC nuclei. Conversely, transfection of hCSCs with a plasmid carrying Smyd3 was coupled with upregulation of hTERT and hNkx2.5. Chromatin immunoprecipitation assay show that Smyd3 binds to hTERT, hGata6 and hNkx2.5 promoter regions that contains the putative binding sites for Smyd3. Moreover, the mutations at the Smyd3 DNA binding sites, decreased the promoter activity of hTERT and hGata6. Smyd3 siRNA treatment decreased the reporter activity of luciferase reporter plasmids containing hTERT.
Highlights
The phenotypic properties of embryonic and adult stem cells are largely mediated by epigenetic modifications which control stemness, multipotentiality and fate specification
The high levels of di-(H3K4me2) and tri-methylation (H3K4me3) at lysine 4 of histone H3 prompted us to test the function of histone methyltransferase Smyd3, which is downregulated by the non-functional mutation in the c-kit receptor, in human cardiac stem cells (hCSCs)
Attenuation of hCSC growth was coupled with a decline in the expression of telomerase, hTERT, and the myocyte specific transcription factors hNkx2.5 and hGata6
Summary
A histone methyltransferase, modulates the growth and differentiation of human cardiac stem cells. Narasimman Gurusamy1*, Junghyun Kim, Toru Hosoda, Gauthaman Karunakaran, Mubarak Al Gahtany, Annarosa Leri. From 2nd International Genomic Medical Conference (IGMC 2013) Jeddah, Kingdom of Saudi Arabia. From 2nd International Genomic Medical Conference (IGMC 2013) Jeddah, Kingdom of Saudi Arabia. 24-27 November 2013
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