Codon usage, non-coding RNA and circadian clocks
New genetic codes: synonymous genetic codons regulate 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 but its biological functions are not clear. Our previous studies demonstrate that the codon usage bias regulates protein expression and protein function by regulating the speed of translation elongation and co-translational folding. In addition, we uncovered the relationship between codon usage bias and predicted protein structures in fungi and animal systems. Furthermore, we demonstrated that codon usage plays an important role in determining gene expression levels in eukaryotes. Together these results uncovered the existence of unexpected codon usage codes within genetic codons for protein folding and gene expression. Synonoymous codons can have major impact on protein function and protein expression levels without affecting protein sequence. We are now using molecular, biochemical, genetic and bioinformatic approaches to address these fundamental questions.
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.
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. One of the most important characteristics of circadian rhythms is that they can be synchronized or entrained by environmental signals, the strongest of which are light and temperature. 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 crassa, one of the best studied model organisms for circadian clocks, to understand the molecular mechanisms of the circadian clock. In Neurospora, the circadian clock acts to control a variety of processes, and previous studies have shown that the Neurospora circadian clock is an auto-regulated negative feedback loop in which the frequency (frq) gene is an essential component. My laboratory is using molecular, biochemical, and genetic approaches to answer three general questions: 1) What are the components of the input pathways to the clock and how do environmental signals entrain the clock; 2) What are the genes that make up the oscillator and how are they regulated to generate rhythms and 3) How does the clock control rhythmic output events? In the long term, these studies will enable us to compare clock mechanisms of fungi with those of other eukaryotes and to help guide research in other organisms.
- Wuhan University (1989), Biology
- Graduate School
- Vanderbilt University (1995), Biology
- Mechanisms of circadian clocks
- Role of codon usage biases in regulating gene expression and protein structure
- small non-coding RNAs and long non-coding RNAs
- 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
- Codon usage regulates protein structure and function by affecting translation elongation speed in Drosophila cells.
- Zhao F, Yu CH, Liu Y Nucleic Acids Res. 2017 Jun
- Antisense transcription licenses nascent transcripts to mediate transcriptional gene silencing.
- Dang Y, Cheng J, Sun X, Zhou Z, Liu Y Genes Dev. 2016 Nov 30 21 2417-2432
- Codon usage is an important determinant of gene expression levels largely through its effects on transcription.
- Zhou Z, Dang Y, Zhou M, Li L, Yu CH, Fu J, Chen S, Liu Y Proc. Natl. Acad. Sci. U.S.A. 2016 Sep
- Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD.
- Fu J, Murphy KA, Zhou M, Li YH, Lam VH, Tabuloc CA, Chiu JC, Liu Y Genes Dev. 2016 Aug 30 15 1761-75
- Codon Usage Influences the Local Rate of Translation Elongation to Regulate Co-translational Protein Folding.
- Yu CH, Dang Y, Zhou Z, Wu C, Zhao F, Sachs MS, Liu Y Mol. Cell 2015 Aug
- Mechanism of siRNA production from repetitive DNA.
- Yang Q, Ye QA, Liu Y Genes Dev. 2015 Feb
- Transcriptional interference by antisense RNA is required for circadian clock function.
- Xue Z, Ye Q, Anson SR, Yang J, Xiao G, Kowbel D, Glass NL, Crosthwaite SK, Liu Y Nature 2014 Aug
- Non-optimal codon usage affects expression, structure and function of clock protein FRQ.
- Zhou M, Guo J, Cha J, Chae M, Chen S, Barral JM, Sachs MS, Liu Y. Nature 2013 495(7439)
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)