Liu (Yi) Lab | UT Southwestern, Dallas, Texas

Meet the PI

Yi Liu, Ph.D.

Education

Undergraduate: Wuhan University (1989), Biology

Graduate School: Vanderbilt University (1995), Biology

Research Interest

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

UT Southwestern Profile

Research

The Liu Lab is interested in the functions and mechanism of codon usage biases, circadian clocks, and non-coding RNA.

Codon usage biases: new codes within genetic codons

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 can 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. 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. 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.

Publications for Dr. Yi Liu

Featured Publications

Mammalian circadian clock proteins form dynamic interacting microbodies distinct from phase separation.

Xie P, Xie X, Ye C, Dean KM, Laothamatas I, Taufique SKT, Takahashi J, Yamazaki S, Xu Y, Liu Y, 2023 Dec Proc Natl Acad Sci U S A 52 120 e2318274120

Decoupling PER phosphorylation, stability and rhythmic expression from circadian clock function by abolishing PER-CK1 interaction.

An Y, Yuan B, Xie P, Gu Y, Liu Z, Wang T, Li Z, Xu Y, Liu Y, 2022 Jul Nat Commun 1 13 3991

Synonymous but not Silent: The Codon Usage Code for Gene Expression and Protein Folding.

Liu Y, Yang Q, Zhao F, 2021 Jan Annu Rev Biochem

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, 2021 Feb Proc Natl Acad Sci U S A 6 118

Effects of codon usage on gene expression are promoter context dependent.

Yang Q, Lyu X, Zhao F, Liu Y, 2021 01 Nucleic Acids Res 2 49 818-831

A code within the genetic code: codon usage regulates co-translational protein folding.

Liu Y, 2020 09 Cell Commun Signal 1 18 145

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, 2020 06 PLoS Genet 6 16 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, 2019 Sep Nat Commun 1 10 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, 2019 Aug Nucleic Acids Res.

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 2018 Mar Elife 7

Codon usage regulates human KRAS expression at both transcriptional and translational levels.

Fu J, Dang Y, Counter C, Liu Y, 2018 11 J. Biol. Chem. 46 293 17929-17940

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 2017 Jun Mol. Cell

Codon usage regulates protein structure and function by affecting translation elongation speed in Drosophila cells.

Zhao F, Yu CH, Liu Y 2017 Jun Nucleic Acids Res.

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 2016 Sep Proc. Natl. Acad. Sci. U.S.A.

Antisense transcription licenses nascent transcripts to mediate transcriptional gene silencing.

Dang Y, Cheng J, Sun X, Zhou Z, Liu Y 2016 Nov Genes Dev. 21 30 2417-2432

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 2016 Aug Genes Dev. 15 30 1761-75

Nonoptimal codon usage influences protein structure in intrinsically disordered regions.

Zhou M, Wang T, Fu J, Xiao G, Liu Y 2015 Jun Mol. Microbiol.

Mechanism of siRNA production from repetitive DNA.

Yang Q, Ye QA, Liu Y 2015 Feb Genes Dev.

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 2015 Aug Mol. Cell

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 2014 Aug Nature

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 2013 Jan Genes Dev. 2 27 145-50

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. 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. 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 2012 May Mol. Cell 3 46 299-310

The translin-TRAX complex (C3PO) is a ribonuclease in tRNA processing.

Li L, Gu W, Liang C, Liu Q, Mello CC, Liu Y 2012 Jul

RNA interference in fungi: pathways, functions, and applications.

Dang Y, Yang Q, Xue Z, Liu Y 2011 Sep Eukaryotic Cell 9 10 1148-55

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. 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 2010 8/10 e1000496

Setting the pace of the Neurospora circadian clock by multiple independent FRQ phosphorylation events.

Tang CT, Li S, Long C, Cha J, Huang G, Li L, Chen S, Liu Y 2009 Jun Proc. Natl. Acad. Sci. U.S.A. 26 106

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. 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 2009 138 1236-1246

Control of WHITE COLLAR localization by phosphorylation is a critical step in the circadian negative feedback process.

Cha J, Chang SS, Huang G, Cheng P, Liu Y 2008 Dec EMBO J. 24 27

Protein kinase A and casein kinases mediate sequential phosphorylation events in the circadian negative feedback loop.

Huang G, Chen S, Li S, Cha J, Long C, Li L, He Q, Liu Y 2007 Dec Genes Dev. 24 21

QIP, a putative exonuclease, interacts with the Neurospora Argonaute protein and facilitates conversion of duplex siRNA into single strands

Maiti, M., Lee, HC., and Liu, Y. 2007 21(5) 590-600

Molecular mechanism of suppression of circadian rhythms by a critical stimulus.

Huang G, Wang L, Liu Y 2006 Nov EMBO J. 22 25

CKI and CKII mediate the FREQUENCY-dependent phosphorylation of the WHITE COLLAR complex to close the Neurospora circadian negative feedback loop

He, Q., J. Cha, Q. He, H. Lee, Y. Yang, and Y. Liu. 2006 20 2552-2565

The COP9 signalosome regulates the Neurospora circadian clock by controlling the stability of the SCFFWD-1 complex.

He Q, Cheng P, He Q, Liu Y 2005 Jul Genes Dev. 13 19

Molecular mechanism of light responses in Neurospora: from light-induced transcription to photoadaptation.

He Q, Liu Y 2005 Dec Genes Dev. 23 19

Regulation of the Neurospora circadian clock by an RNA helicase

Cheng, P., Q. He, Q. He, L. Wang, and Y. Liu. 2005 19 234-241

Distinct roles for PP1 and PP2A in the Neurospora circadian clock.

Yang, Y., Q. He, P. Cheng, P. Wrage, O. Yarden, and Y. Liu. 2004 18 255-260

FWD1-mediated degradation of FREQUENCY in Neurospora establishes a conserved mechanism for circadian clock regulation.

He Q, Cheng P, Yang Y, He Q, Yu H, Liu Y 2003 Sep EMBO J. 17 22

Functional conservation of light, oxygen, or voltage domains in light sensing.

Cheng P, He Q, Yang Y, Wang L, Liu Y 2003 May Proc. Natl. Acad. Sci. U.S.A. 10 100

White Collar-1, a circadian blue light photoreceptor, binding to the frequency promoter.

Froehlich AC, Liu Y, Loros JJ, Dunlap JC 2002 Aug Science 5582 297 815-9

Regulation of the Neurospora circadian clock by casein kinase II

Yang, Y., P. Cheng, and Y. Liu. 2002 15 994-1006

White Collar-1, a DNA-binding transcription factor and a light sensor

He, Q.*, P. Cheng*, Y. Yang, L. Wang, K. H. Gardner, and Y. Liu 2002 297 840-843

Interlocked feedback loops contribute to the robustness of the Neurospora circadian clock.

Cheng P, Yang Y, Liu Y 2001 Jun Proc. Natl. Acad. Sci. U.S.A. 13 98

Coiled-coil domain-mediated FRQ-FRQ interaction is essential for its circadian clock function in Neurospora.

Cheng P, Yang Y, Heintzen C, Liu Y 2001 Jan EMBO J. 1-2 20

Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer.

Huang F, Huffman KE, Wang Z, Wang X, Li K, Cai F, Yang C, Cai L, Shih TS, Zacharias LG, Chung A, Yang Q, Chalishazar MD, Ireland AS, Stewart CA, Cargill K, Girard L, Liu Y, Ni M, Xu J, Wu X, Zhu H, Drapkin B, Byers LA, Oliver TG, Gazdar AF, Minna JD, DeBerardinis RJ, 2021 Jan J Clin Invest 1 131

IMITATION SWITCH is required for normal chromatin structure and gene repression in PRC2 target domains.

Kamei M, Ameri AJ, Ferraro AR, Bar-Peled Y, Zhao F, Ethridge CL, Lail K, Amirebrahimi M, Lipzen A, Ng V, Grigoriev IV, Schmitz RJ, Liu Y, Lewis ZA, 2021 Jan Proc Natl Acad Sci U S A 4 118

High-throughput discovery of genetic determinants of circadian misalignment.

Zhang T, Xie P, Dong Y, Liu Z, Zhou F, Pan D, Huang Z, Zhai Q, Gu Y, Wu Q, Tanaka N, Obata Y, Bradley A, Lelliott CJ, Nutter LMJ, McKerlie C, Flenniken AM, Champy MF, Sorg T, Herault Y, Angelis MH, Durner VG, Mallon AM, Brown SDM, Meehan T, Parkinson HE, Smedley D, Lloyd KCK, Yan J, Gao X, Seong JK, Wang CL, Sedlacek R, Liu Y, Rozman J, Yang L, Xu Y, 2020 Jan PLoS Genet. 1 16 e1008577

Impaired function of the suprachiasmatic nucleus rescues the loss of body temperature homeostasis caused by time-restricted feeding.

Zhang Z, Zhai Q, Gu Y, Zhang T, Huang Z, Liu Z, Liu Y, Xu Y, 2020 Aug Sci Bull (Beijing) 15 65 1268-1280

Nonoptimal Codon Usage Is Critical for Protein Structure and Function of the Master General Amino Acid Control Regulator CPC-1.

Lyu X, Liu Y, 2020 10 mBio 5 11

Histone H3K56 acetylation is required for quelling-induced small RNA production through its role in homologous recombination.

Zhang Z, Yang Q, Sun G, Chen S, He Q, Li S, Liu Y 2014 Feb J. Biol. Chem.

The Ccr4-Not complex regulates the phase of the Neurospora circadian clock by controlling WHITE COLLAR protein stability and activity.

Huang G, He Q, Guo J, Cha J, Liu Y 2013 Sep J. Biol. Chem.

Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock.

Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, Wang X, Gao X, Huang M, Yan J, Yang L, Liu Y, Ptácek LJ, Xu Y 2013 Mar Proc. Natl. Acad. Sci. U.S.A. 12 110 4750-5

Transcription of the major neurospora crassa microRNA-like small RNAs relies on RNA polymerase III.

Yang Q, Li L, Xue Z, Ye Q, Zhang L, Li S, Liu Y 2013 Jan PLoS Genet. 1 9 e1003227

CATP is a critical component of the Neurospora circadian clock by regulating the nucleosome occupancy rhythm at the frequency locus.

Cha J, Zhou M, Liu Y 2013 Aug EMBO Rep.

Convergent Transcription Induces Dynamic DNA Methylation at disiRNA Loci

Dang Y, Li L, Guo W, Xue Z, Liu Y. 2013 PLoS Genet. Sep;9(9):e1003761

RNA Interference Pathways in Fungi: Mechanisms and Functions.

Chang SS, Zhang Z, Liu Y 2012 Jun

Regulation of the activity and cellular localization of the circadian clock protein FRQ.

Cha J, Yuan H, Liu Y 2011 Apr J. Biol. Chem. 13 286 11469-78

Functional significance of FRH in regulating the phosphorylation and stability of Neurospora circadian clock protein FRQ.

Guo J, Cheng P, Liu Y 2010 Apr J. Biol. Chem. 15 285 11508-15