The designer of gene expression: an approach for the development of artificial transcription networks to regulate gene expression ad libitum


Transcription, the synthesis of messenger RNA from the corresponding gene locus, is one of the most fundamental biological processes in all living things. In multi-cellular organisms, thousands of genes are expressed in a single cell, but the “set of genes” expressed in one differentiated cell may be different from another. Therefore, regulation of gene expression may be synonymous with cell differentiation during development. Although the recent discovery of only four transcription factors: Oct4, Sox2, KLF3 and Myc, which can reprogram differentiated cells into induced pluripotent stem (iPS) cells, indicates that we are able to control cell differentiation ad libitum, although such regulation is difficult using current technologies. Thus it is necessary to study deeply and understand the complex interaction between cis- and trans-acting factors. For example, the structure of basal, or core promoters, as engines of the transcription machinery of eukaryotes (which is composed of the common cis-elements and their corresponding trans-acting factors) has been well-documented because it is evolutionarily conserved and located close to the transcription start site of the corresponding downstream gene. In most cases, however, the principle of cell-type specific gene expression is still incomprehensible because such cell-type specific enhancers (or silencers) were hidden in the illimitable woods of genome sequences. The recent revolution in sequencing technologies spawned a huge quantity of whole genome data in a short period of time at a reasonable cost. With comparative genome analyses utilizing new sequencing technologies and bioinformatics, we hope to elucidate the principle of tissue- or cell type- specific gene expression in multi-cellular organisms. Our goal is to establish a novel discipline, “promoter engineering,” in order to provide a framework for designing artificial transcription systems. We have proceeded with the following projects:

  1. Development of computational analysis by comparing regulatory regions between microbes and man using the massively parallel next-generation sequencer.
  2. Characterization and modification of small, addorsed bidirectional (SAB) and cell-type specific (e.g. neuron-specific) promoters by comparing regulatory regions between related species which have counterfeit genomes of the Japanese rice fish Medaka (Oryzias latipes).
  3. Implementation and verification of artificial transcription networks introduced into cells or living organisms designed to optimize gene expression ad libitum by combining modified genes, cis-acting regulatory regions, trans-acting factors, and non-coding RNAs.