From the September Edition of Stem Cells
By Stuart P. Atkinson
Generation of induced pluripotent stem cells (iPSCs) is both slow and inefficient; the route from somatic target cell generally takes a minimum of 4 weeks and only 1 in a thousand target cells being reprogrammed. The proper reconfiguration of the chromatin landscape is deemed a potential obstacle in the reprogramming process; so much so that small molecule inhibitors which promote a more open chromatin configuration are becoming common place in many reprogramming protocols (Huangfu, Maehr et al and Huangfu, Osafune et al). One potential problem with this approach is the lack of specific chromatin changes; instead these inhibitors promote global chromatin changes. Specific chromatin changes occur due to the specific recruitment of epigenetic regulators to specific loci by transcription factors; and so this suggests that currently used transcription factors in reprogramming (Oct4, Sox2, Klf4, Myc and Nanog) may have limited means to reconfigure chromatin. Myod1 is a master transcription factor for skeletal myogenesis and can directly convert one cell type into another, as exemplified by its ability to generate myotubes from pigmented retinal epithelial cells (Choi et al). This suggests that Myod1 has a more potent ability to recruit epigenetic modifiers leading to activation of suppressed genes embedded in closed chromatin. This hypothesis has been now been tested by the laboratory of from the Stem Cell Institute, University of Minnesota, USA and Laboratory of Animal Reproduction, Kinki University, Nara, Japan and is presented in the September Edition of Stem Cells (Hirai et al). Full-length mouse Oct4 (O) was fused with various fragments of mouse Myod1, excluding the basic helix-loop-helix (bHLH) domain to avoid activation of Myod1 target genes, and were co-transduced with a polycistronic retroviral vector encoding mouse Sox2, Klf4, and Myc (SKM) into MEFs derived from Oct4-GFP mice, allowing for the monitoring of the reprogramming process. Using this system, the authors demonstrate that that a specific chimeric Oct4-Myod1 protein can reprogram MEFs to an iPSC state more efficiently than OSKM.