title: Ezh2 mediated H3K27me3 activity facilitates somatic transition during human pluripotent reprogramming.
abstract: Factor induced reprogramming of fibroblasts is an orchestrated but inefficient process. At the epigenetic level, it results in drastic chromatin changes to erase the existing somatic "memory" and to establish the pluripotent state. Accordingly, alterations of chromatin regulators including Ezh2 influence iPSC generation. While the role of individual transcription factors in resetting the chromatin landscape during iPSC generation is increasingly evident, their engagement with chromatin modulators remains to be elucidated. In the current study, we demonstrate that histone methyl transferase activity of Ezh2 is required for mesenchymal to epithelial transition (MET) during human iPSC generation. We show that the H3K27me3 activity favors induction of pluripotency by transcriptionally targeting the TGF-β signaling pathway. We also demonstrate that the Ezh2 negatively regulates the expression of pro-EMT miRNA's such as miR-23a locus during MET. Unique association of Ezh2 with c-Myc was required to silence the aforementioned circuitry. Collectively, our findings provide a mechanistic understanding by which Ezh2 restricts the somatic programme during early phase of cellular reprogramming and establish the importance of Ezh2 dependent H3K27me3 activity in transcriptional and miRNA modulation during human iPSC generation.
authors: 1] 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.
authors: Radhika Arasala
authors: RA
authors: Rao
authors: 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.
authors: Narendra
authors: N
authors: Dhele
authors: Department of Hematology and Centre for Stem Cell Research, Christian Medical College, Vellore - 632004, TamilNadu, India.
authors: Sabna
authors: S
authors: Cheemadan
authors: 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.
authors: Alhad
authors: A
authors: Ketkar
authors: Department of Hematology and Centre for Stem Cell Research, Christian Medical College, Vellore - 632004, TamilNadu, India.
authors: Giridhara R
authors: GR
authors: Jayandharan
authors: 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.
authors: Dasaradhi
authors: D
authors: Palakodeti
authors: 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.
authors: Shravanti
authors: S
authors: Rampalli
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D065150:Cellular Reprogramming; D000071221:Enhancer of Zeste Homolog 2 Protein; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D006657:Histones; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D018125:Receptors, Transforming Growth Factor beta; D055748:SOXB1 Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D019859:Proto-Oncogene Proteins c-met
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