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Identification of Mechanism for Gene Expression Regulation by Transcripts and Translators at Genome Level

Identification of Gene Structure in Actinomycetes Using Next-Generation Research Technology

This study was conducted to identify the overall flow of gene expression from primary transcripts to transcripts to translators by applying three types of next-generation sequencing technology, transcription start point sequencing, RNA sequencing, and ribosome profiling, and conducting a comprehensive analysis. The three techniques correspond to the growth stages of actinomycetes, a kind of microorganism used for the biosynthesis of antibiotics. Actinomycetes have around 200 secondary metabolites involved in various antibiotic biosynthesis. The biosynthesis of these metabolites includes a physiological change from primary metabolism to secondary metabolism as well as morphological differentiation, based on a regulatory mechanism linking transcription, translation, and post-translation. The research team of professor Cho Byung-Kwan conducted a comprehensive analysis based on the “sequencing of gene expression initiation points,” which is a technology for detecting the first position where RNA is synthesized from DNA; and an analysis of “ribosome-binding RNA sequencing data,” which can be used to observe whether a gene is actually translated into a protein. Professor Cho commented that this study resulting in the clarification of the gene-regulating mechanism of actinomycetes, and a large amount of data was secured which can be utilized in manipulating the genome of actinomycetes for the mass production of various antibiotics. Summarizing the study, professor Cho explained, “The study aimed to show the overall flow of gene expression by applying three analysis techniques of the next-generation sequencing technology, which is developing at a rapid pace, based on the growth stages of S. coelicolor, one type of actinomycetes, and by performing a system-level analysis on the results of their application. The three analysis techniques applied in this study are the sequencing of gene expression initiation points, RNA sequencing, and ribosome binding RNA sequencing. Further, the study identified and secured various genetic data which can be used to build an actinomycete cell plant for the mass production of antibiotics, through the sequencing of gene expression initiation points. This study demonstrated that the genes related to antibiotic biosynthesis are regulated during the translation of the protein from mRNA.

Age of Mass Production of Antibiotics

Genetic structure information obtained at the genome level was used to compare gene expressions between the levels of transcription and translation. As a result of the comparison, a phenomenon known as translational buffering was found. This means that the translation rate at which protein is produced from mRNA, is significantly slower than the transcription rate at which mRNA is made from DNA. This indicates that it is necessary to consider not only the level of transcription but also the level of translation when constructing an actinomycete cell plant capable of mass production of antibiotics. Based on the expression patterns of the genes that specifically control the antibiotic gene cluster, it was learned that while the quantity of transcripts increased steadily with the growth stages, the level of translation increased rapidly only at a certain stage of growth. These findings showed that antibiotic biosynthetic regulatory genes can be regulated at a certain stage of growth by the level of translation, and this understanding is expected to be useful when a cell plant for the mass production of antibiotics is to be built. “Since the genome of actinomycetes has a very high content of GC, general molecular biology techniques did not work well in most cases. So we struggled to optimize each next-generation sequencing technology for its application to actinomycetes,” said professor Cho. He noted that, “Based on the results of this study, we will aim to establish foundations for the mass production and commercialization of high-value-added compounds.” In particular, the results of this study represent a step forward in the era of mass production of antibiotics. The information gained on the entire genome level through the use of various next-generation sequencing techniques will be an important reference for future molecular genetic and systematic studies. Also, a great deal of the collected information on the DNA structure and on transcripts and translators can be used for the construction of an actinomycete cell plant, and is expected to be useful in selecting engineering targets. Further, this study also opens the possibility of increasing the production of antibiotics using synthetic biology technology, by engineering the genes regulating the biosynthesis of antibiotics, which are controlled by the translation level. The findings of this study were published June 2in the online edition of Nature Communications dated, the leading authoritative biotechnology journal.

Prof. Cho, Byung-Kwan
2016 Annual Report

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