Molecular Mechanisms of Somatic Cell Reprogramming
Somatic cell reprogramming has enabled the generation of induced pluripotent stem cells (iPSCs). IPSCs can be used in disease modeling and derivation of rejection-free mature cell types for cell-replacement therapies. Despite their immense potential, technical obstacles remain in the generation of iPSCs for clinical purposes. Our research is aimed at generating tools to overcome these obstacles by elucidating the molecular mechanisms of reprogramming and identifying genes that play important roles in iPSC generation. To discover such genes we are utilizing a combination of candidate-based and high-throughput molecular approaches.
To address how chromatin-modifying proteins influence the reprogramming process, we used shRNAs to target genes in DNA and histone methylation pathways, and have identified positive and negative regulatorsof iPSC generation. Specifically, inhibition of Dot1L, the H3K79 histonemethyltransferase, either by RNAi or a small molecule inhibitoraccelerated reprogramming, significantly increased the yield of iPSC colonies, and substituted for Klf4 and c-Myc in the reprogramming cocktail. Genome-wide analysis of H3K79me2 distribution by ChIP-sequencing revealed that fibroblast-specific genes associated with the epithelial to mesenchymal transition lose H3K79me2 in the initial phases of reprogramming. Dot1L inhibition facilitates the loss of this mark from genes that are fated to be repressed in the pluripotent state. These findings implicate specific chromatin-modifying enzymes as barriers to reprogramming, and demonstrate how modulation of chromatin-modifying enzymes can be exploited to more efficiently generate iPSCs with fewer exogenous transcription factors.
Tamer ÖNDER Short Bio
Dr. Tamer T. Önder was born in 1980 in Istanbul. He graduated from Robert College in 1998 and went to the US to attend Cornell University in Ithaca, NY. There, he double majored in molecular biology and genetics and European history, graduating magna cum laude (with high honors) in 2002. From there he moved to Boston, where he went to graduate school in Biology at the Massachusetts Institute of Technology (MIT). At MIT, Dr. Önder completed his thesis work on cancer metastasis and cancer stem cells under the supervision of Prof. Robert Weinberg at the Whitehead Institute. From 2008-2012 Dr. Önder was a postdoctoral research fellow in Prof. George Daley's group at the Harvard Medical School and Children's Hospital Boston Hematology and Oncology department where he studied somatic cell reprogramming and induced pluripotent stem (iPS) cells . Dr. Önder's work on cancer biology and stem cells has been published in several peer-reviewed journals such as PNAS, Cell and Nature. Since 2012, Dr. Önder is an assistant professor at Koç University School of Medicine and his current research focuses on molecular mechanism of reprogramming and generation of patient-specific iPS cells.