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 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.
- Wuhan University (1989), Biology
- Graduate School
- Vanderbilt University (1995), Biology
- New genetic codes, Mechanisms of circadian clocks, non-coding RNA
- Role of codon usage biases in regulating gene expression and protein structure
- small non-coding RNAs and long non-coding RNAs
- Genome-wide role of codon usage on transcription and identification of potential regulators.
- Zhao F, Zhou Z, Dang Y, Na H, Adam C, Lipzen A, Ng V, Grigoriev IV, Liu Y, Proc Natl Acad Sci U S A 2021 Feb 118 6
- Synonymous but not Silent: The Codon Usage Code for Gene Expression and Protein Folding.
- Liu Y, Yang Q, Zhao F, Annu Rev Biochem 2021 Jan
- Effects of codon usage on gene expression are promoter context dependent.
- Yang Q, Lyu X, Zhao F, Liu Y, Nucleic Acids Res 2021 01 49 2 818-831
- A code within the genetic code: codon usage regulates co-translational protein folding.
- Liu Y, Cell Commun Signal 2020 09 18 1 145
- Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape.
- Lyu X, Yang Q, Li L, Dang Y, Zhou Z, Chen S, Liu Y, PLoS Genet 2020 06 16 6 e1008836
- FRQ-CK1 interaction determines the period of circadian rhythms in Neurospora.
- Liu X, Chen A, Caicedo-Casso A, Cui G, Du M, He Q, Lim S, Kim HJ, Hong CI, Liu Y, Nat Commun 2019 Sep 10 1 4352
- eRF1 mediates codon usage effects on mRNA translation efficiency through premature termination at rare codons.
- Yang Q, Yu CH, Zhao F, Dang Y, Wu C, Xie P, Sachs MS, Liu Y, Nucleic Acids Res. 2019 Aug
- Codon usage regulates human KRAS expression at both transcriptional and translational levels.
- Fu J, Dang Y, Counter C, Liu Y, J. Biol. Chem. 2018 11 293 46 17929-17940
- Codon usage biases co-evolve with transcription termination machinery to suppress premature cleavage and polyadenylation.
- Zhou Z, Dang Y, Zhou M, Yuan H, Liu Y Elife 2018 Mar 7
- DNA Replication Is Required for Circadian Clock Function by Regulating Rhythmic Nucleosome Composition.
- Liu X, Dang Y, Matsu-Ura T, He Y, He Q, Hong CI, Liu Y Mol. Cell 2017 Jun
Honors & Awards
- 1998 - 1999
NIH National Research Service Award for Individual Postdoctoral Fellows (0)
- 1999 - 2003
Louise W. Kahn Endowed Scholar in Biomedical Research (0)
The Beadle and Tatum Award (0)