Transcription Factor of Mediated Epigenetic Reprogramming

The basic leucine zipper transcription factor C/EBPa, required for the in vivo transition of common myeloid progenitor-to-GM progenitor. Myelomonocyte cell-type features are educed by the ectopic expression of C/EBPa in primary bone marrow cells, lymphocytes or in fibroblasts, where C/EBPa function along with PU.1, as deposition of H3K4me1 at enhancer elements of target genes demand this.

Pax5 gets induced by the differentiation of CLPs to B-cell lineage rely on the TFs PU.1, E2A, and EBF1 which activates B-cell specific genes meanwhile repressing genes associated with different lineages. B-lymphopoiesis cannot be accomplished by Pax5-/- pro-B-cells but can differentiate into other hematopoietic cell types in response to explicit signalling cascades. When Pax5 is removed from mature B-cells it will result in dedifferentiation to uncommitted progenitor cell population, which will then undergo T-lymphopoiesis. If the sequential expression of C/EBPa and GATA-2 in GM progenitors is altered then, the commitment will also change.

Conversion of exocrine pancreas tissue to insulin-secreting endocrine ß-cells in vivo can be done by force expression of three bHLH TFs, Ngn3, Pdx1, and MafA, which were identified by Melton and co-workers. When hepatic progenitor cells are introduced with expression of only the endocrine progenitor-defining TF Ngn3, it generated physiologically responsive pancreatic endocrine cells. But, in the case of mature hepatocytes in place of hepatic progenitor cells, only insulin expression in islet cells was induced. TFs Atoh1 and Prox1 were found to be the one who modulate sensory hair cells and other supporting cells development, which are from a common progenitor. Non-sensory cells of cochlea were converted to sensory hair cells due to ectopic expression of Atoh1. But, cellular degeneration occurred due to suppression of Gfi1 and Atoh1, which are important for sensory cells specification, by expression of Prox1.

Besides inactivation of p19Arf, ectopic expression of GATA-4, Hnf1a, and Foxa3 in fibroblasts can give hepatocyte like cells. In murine adult or embryonic fibroblasts can be induced as multiple hepatocyte, by the ectopic expression of Hnf4a and one of the three foxA genes.

Yamanaka and Melton, Wernig and co-workers shown that, the expression of three factors, Ascl1, Brn2 and Myt1l, in murine embryonic and postnatal fibroblasts induced transformation to neural (induced neuronal/iN) cells, which are physiologically responsive and able to constitute functional synapses. Neuronal differentiation of human ESCs can be possibly induced by those three factors but, supplementary co-expression of NeuroD1 is needed for reprogramming of human fetal fibroblasts to functional iN cells. Lately Marro reprogrammed murine hepatocytes into iN cells, to show neural conversion of a differentiated non-ectodermal cell type. iN cells keep limited epigenetic signature of their starting state and hepatic transcriptome is repressed. To functional neural subtypes such as dopaminergic neurons and spinal motor neurons human and mouse fibroblasts reprogramming can be done. Fibroblasts can be enticed to explicit neural lineage markers and demonstrate neuronal morphology entirely by forced expression of microRNAs miR-9/9* and miR-124, which restrain the Baf53a subunit of the BAF chromatin-remodelling complex, with the expression of another two additional TFs. Because number of reprogrammed cells became post-mitotic within 24 hours of factor induction, reprogramming occurs in absence of continued cell division.

Generation of a variety of neuronal cells and cardiac muscle cells efficiently from ESCs or non-cardiac somatic is a big advancement in the field of translational medicine. It was evident for the first time of converting a non-cardiogenic tissue to cardiac type, when a mice embryo was transfected with transcriptional regulator, which is required for development of cardiac cell types. Works of Srivastava and co-workers has shown that induced cardiomyocytes can be generated by reprogramming of embryonic and adult fibroblasts using TFs GATA-4, Mef2C, and Tbx5.

This TF-mediated reprogramming generates variety of cell types, which can be used in therapeutics, but requires more exploration. But the stability and comparative termination of functional, transcriptional, and epigenetic remodelling, and the in vivo equivalence of the generated cell types, remain unclear. By understanding the risks posed by incomplete reprogramming or cellular memory is an indicator of the translational application of induced cell types.

c-Myc is not a core member of the ESC pluripotency network, but it is frequently included in the reprogramming factor mixture, and expression c-Myc gene improve the efficiency of somatic cell reprogramming. Network controlled by this gene, basically comprise targets involved in metabolic, cell cycle, and proliferative processes which is separated greatly from core ESC pluripotency network. c-Myc target gene promoters are eminently enriched for the active histone modification H3K4me3 and depleted of the repressive modification H3K27me3 in ESCs.