Yi Liu, Ph.D.

Codon usage, circadian clocks and non-coding RNA 

New codes within genetic codons: codon usage regulates protein structure and gene expression

Most amino acids are encoded by two to six synonymous codons. Preferential use of certain synonymous codons, a phenomenon called codon usage bias, was found in all genomes. We demonstrate that synonymous codons have major impact on protein function and protein expression levels without affecting protein amino acid sequence.  Codon usage regulates protein structure and function by regulating the speed of translation elongation and co-translational folding process. In addition, codon usage bias and predicted protein structures correlate in fungi and animal systems. On the other hand, we discovered that codon usage plays an important role in determining gene expression levels in fungi and mammalian cells not only by affecting mRNA translation efficiency but also surprisingly by regulating gene transcription. Together these results uncovered the existence of unexpected codon usage codes within genetic codons for protein folding and gene expression. Our results also suggest that synonymous mutations can be a cause for human diseases without affecting amino acid sequences. We are now using molecular, biochemical, genetic and systems biology approaches to address these fundamental questions in fungi and animals.

Circadian clock

Circadian clocks have been described in almost all organisms ranging in complexity from single cells to mammals and function to control daily rhythms in a variety of biochemical, cellular, physiological and behavioral events. These rhythms have a period close to 24 hours (circadian) and persist in the absence of external time cues. In humans and mammals, circadian clocks control events such as sleep-wake and activity cycles, body temperature cycles, endocrine functions, and gene expression. Clinical consequences in humans including sleep disorders and depression can be observed when the clock malfunctions. The influence of a functional clock on temporal regulation is evident from the decreased performance of shift workers and the jet lag felt by long distance travelers.

Our lab is using filamentous fungus Neurospora, which has a circadian clock similar to those of animals, to understand the molecular mechanisms of circadian clock. Our research on the circadian clock has focused on the circadian oscillator mechanism and has resulted in the identification of many new clock genes and uncovered several new regulatory mechanisms in circadian clocks. We established a molecular and biochemical model for the circadian feedback loop that involves post-translational and post-transcriptional regulation as important processes. We discovered and characterized a phosphorylation/ubiquitination pathway, which is the major mechanism that determines clock period length. Furthermore, we discovered a novel circadian light-signaling pathway that is now understood from the photoreceptor to the mechanism of light-induced transcriptional activation.

RNA interference and small non-coding RNAs

The production of double-stranded RNA (dsRNA) or small non-coding RNAs is known to elicit RNA interference (RNAi) in most eukaryotes. RNAi and related pathways are evolutionarily conserved gene silencing mechanisms that regulate gene expression, development, genome stability, and host-defense responses from fungi to human. The filamentous fungus Neurospora crassa, an organism that broadly employs gene silencing in regulation of gene expression, offers a unique and powerful system for understanding the RNAi pathway, small RNA production, and its function in eukaryotes. Using Neurospora as a model system, we have revealed the mechanism of the RISC activation process in the RNAi pathway. We also showed that dsRNA activates a novel signaling pathway to induce transcription of many genes in Neurospora, including most of the RNAi components, putative antiviral genes, and homologs of the interferon stimulated genes. In addition, we have uncovered several novel small RNA production pathways in this organism that are conserved in higher eukaryotes. Our current research is focusing on the understanding of the biogenesis pathways of small non-coding RNAs, regulation of RNAi components and on the involvement of RNAi pathway in various cellular processes.