Small activating mRNA (samRNA): A hypothesis for a specific positive feedback regulation of gene expression

Small interference RNAs (siRNAs) target their corresponding mRNAs or homologous genomic DNA sequences to induce gene silencing for down-regulation of gene expressions. In contrast, how the cells can sense the requirement for a gene expression and specifically activate its expression remains a puzzle. We hypothesize that an mRNA fragment-regulated process is a common mechanism for a specific positive feedback regulation of gene expression. We rationalize that a gene's own mRNA degradative product can positively regulate its expression through sequence specific interaction with the genomic DNA at the transcription initiation site. When an mRNA translates to a protein, it degrades into small fragments. These mRNA fragments, especially the 5′ capped RNA fragments, are subjected to cytoplasm-nucleus shuttling, providing a spatial and temporal regulation of a gene. These mRNA fragments are defined as a “small activating mRNA (samRNA).” The samRNA acts as a sensor and a stimulator for its own gene expression, which play an active role in the specific positive feedback regulation of the gene expression. As such, siRNA and samRNA provide a “yin” (negative regulation) and “yang” (positive regulation) regulation for gene expression. Establishment of the novel technology platform built upon the samRNA-mediated positive regulation mechanism will enable therapeutic induction of the gene expression in gene therapy, aging prevention, guided stem cell differentiation, and reprogramming of the human mature cells into induced pluripotent cells.