A Ribosome-Mediated Genetic Circuit for New Therapies

Gene expression rests on two fundamental processes. Within a cell’s nucleus, segments of DNA encode messenger RNAs (mRNAs) during transcription. mRNAs then carry the genetic information from the cell’s nucleus into the cytoplasm, where ribosomes build proteins based on the information in a process called translation. Transcription and translation happen on opposite sides of the nuclear membrane, and until recently, scientists thought that few opportunities existed for feedback between the two processes. New evidence, however, suggests that if ribosomes encounter aberrant genetic sequences during translation in the cytoplasm, the transcription of sequences with similar functions rapidly increases in the nucleus as if to compensate for the aberrant ones.

Shu-Bing Qian, Nutritional Sciences, is investigating the possibility that ribosomes and short fragments of mRNA are part of a genetic circuit that facilitates communication between nuclear transcription and cytoplasmic translation, making possible this compensatory upregulation of similar genes. To characterize this genetic circuit, Qian is using a new technology called EZRA-seq, developed by the Qian lab, to rapidly sequence very short mRNA fragments. Qian hypothesizes that these short mRNA fragments influence gene expression in a sequence-dependent manner—acting as part of a ribosome-mediated genetic circuit that supports genetic robustness and adaptative responses to stressors.

The discovery of a ribosome-mediated genetic circuit would transform central tenets of molecular biology. Dysfunctions in gene expression can lead to a variety of diseases, including diabetes and cancer, and this research will explore the potential of using artificial mRNA sequences to regulate gene expression, opening avenues toward new therapeutic strategies.

NIH Award Number: 1DP1GM142101-01

Cornell Researchers

Funding Received

$5.4 Million spanning 5 years