Molecular Mechanisms of Small non-coding RNAs and Circadian Clocks
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 - China (1989)
- Graduate School
- Vanderbilt University (1995)
- epigenetic regulation
- Mechanisms of circadian clocks
- RNA interference and gene silencing
- small non-coding RNAs and long non-coding RNAs
- The role of codon usage in regulating protein expression and structure
- 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
- Homologous recombination as a mechanism to recognize repetitive DNA sequences in an RNAi pathway.
- Zhang Z, Chang SS, Zhang Z, Xue Z, Zhang H, Li S, Liu Y Genes Dev. 2013 Jan 27 2 145-50
- 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)
- Non-optimal codon usage is a mechanism to achieve circadian clock conditionality.
- Xu Y, Ma P, Shah P, Rokas A, Liu Y, Johnson CH. Nature 2013 495(7439)
- Reconstitution of an Argonaute-Dependent Small RNA Biogenesis Pathway Reveals a Handover Mechanism Involving the RNA Exosome and the Exonuclease QIP.
- Xue Z, Yuan H, Guo J, Liu Y Mol. Cell 2012 May 46 3 299-310
- Diverse pathways generate microRNA-like RNAs and Dicer-independent small interfering RNAs in fungi.
- Lee, H.C, L. Li, W. Gu, Z. Xue, S. K. Crosthwaite, A. Pertsemlidis, Z. A. Lewis, M. Freitag, E.U. Selker, C.C. Mello, and Y. Liu. Molecular Cell (cover article) 2010 38 803-814 (cover article)
- The DNA/RNA-dependent RNA polymerase QDE-1 generates aberrant RNA and dsRNA for RNAi in a process requiring Replication Protein A and a DNA helicase
- Lee, H.C., A.P. Aalto, Q. Yang, S. Chang, G. Huang, D. Fisher, J. Cha, M.M. Poranen, D.H. Bamford and Y. Liu PloS Biology 2010 8/10 e1000496
- qiRNA is a new type of small interfering RNA induced by DNA damage
- Lee HC, Chang SS, Choudhary S, Aalto AP, Maiti M, Bamford DH, Y. Liu. Nature (cover article) 2009 459 274-277. Cover Article
- The Exosome Regulates Circadian Gene Expression in a Posttranscriptional Negative Feedback Loop
- Guo J, Cheng P, Yuan H and Y Liu Cell 2009 138 1236-1246
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)