Mechanisms of reprogramming to pluripotency induced by exogenous transcription factors and hypothetical mechanisms of small molecule-mediated reprogramming to pluripotency
A. Somatic cell maintains its identity by transcription factor (TF) mediated activation of lineage specific genes, and TF or heterochromatin mediated silencing of pluripoteny genes.
B. In the paradigm of TF-induced reprogramming to pluripotency, exogenous reprogramming TF complexes (e.g., pluripotency TF complexes coming from oocyte in SCNT, pluripotent cell in cell fusion, or ectopically expressed iPSC TFs), which can recognize and bind to specific sequences across the whole genome, interact with other TFs binding to nearby or distal sites and recruit other transcription cofactors (e.g., activators, repressors, and epigenetic enzyme complexes) to co-occupy and epigenetically modify the genome in a sequence-specific manner. As a result, the gene expression profile and epigenetic pattern of somatic cells gradually becomes iPSC specific. C. Unlike TFs, small molecules do not have the exquisite ability of molecular recognition possessed by TFs, and cannot specifically interact with both DNA and other transcription cofactors. Consequently, small molecules would hypothetically target endogenous components (e.g., TFs in purple and epigenetic enzyme complexes in light blue) in somatic cells to indirectly initiate iPSC reprogramming.
D. Pluripotent stem cell generated by either a TF or small-molecule approach maintains its pluripotency by TF-mediated activation of pluripoteny genes and repression of lineage specific genes.