Andrew Millar (scientist)

Last updated

Andrew J. Millar
Born
London
NationalityBritish
Alma mater University of Cambridge, The Rockefeller University
Known for circadian rhythm, TOC1, bioluminescence imaging, Modelling biological systems
Awards Fellow of the Royal Society, FRSE, EMBO member
Scientific career
Fields Systems Biology, Plant Science, Chronobiology, Data Management.
Institutions University of Virginia, University of Warwick, University of Edinburgh
Thesis  (1994)
Doctoral advisor Nam-Hai Chua, FRS
Other academic advisors Steve A. Kay, Gene D. Block
Website http://www.amillar.org

Andrew John McWalter Millar, FRS, FRSE is a Scottish chronobiologist, systems biologist, and molecular geneticist. Millar is a professor at The University of Edinburgh and also serves as its chair of systems biology. Millar is best known for his contributions to plant circadian biology; in the Steve Kay lab, he pioneered the use of luciferase imaging to identify circadian mutants in Arabidopsis . Additionally, Millar's group has implicated the ELF4 gene in circadian control of flowering time in Arabidopsis. Millar was elected to the Royal Society in 2012 and the Royal Society of Edinburgh in 2013.

Contents

Life

Andrew Millar was raised in Luxembourg. He later attended Cambridge University where he received a Bachelor of Arts in 1988, studying genetics and winning University Prizes for botany in 1987 and genetics in 1988. After graduation, he began doctoral study in the United States at The Rockefeller University under the mentorship of Nam-Hai Chua, FRS, and graduated in 1994 with a PhD in plant molecular genetics. [1] He then completed a postdoctoral fellowship at the National Science Foundation (NSF) Center for Biological Timing at the University of Virginia under the guidance of Steve A. Kay and Gene D. Block in 1995. In 1996, he joined the faculty of the University of Warwick, where he began to work on synthetic and systems biology in conjunction with plant chronobiology. He remained at Warwick until 2005, when he joined the faculty at The University of Edinburgh. Millar helped found SynthSys, a centre for synthetic and systems biology research partnered with the University of Edinburgh, in 2007. [2]

Research

Luciferase and plant circadian biology

As a pioneering chronobiologist, Millar is known for his use of luciferase reporters for the purpose of studying plant circadian biology. Millar began experimenting with the firefly luciferase reporter gene as a graduate student at The Rockefeller University. In 1992, Millar and colleagues fused the Arabidopsis cab2 promoter and the firefly luciferase gene to establish a real-time reporter for circadian-regulated gene expression in plants. Millar tracked the rhythm of transcription from the cab2 promoter using a low-light video imaging system which tracks luciferase bioluminescence. Millar hypothesized that this model could be used to isolate mutants in the plant circadian clock.

In 1995, Millar and colleagues used this luciferase model to identify mutant Arabidopsis plants with abnormal cycling patterns. Millar's group found cab2 expression to oscillate with a shorter period in toc1 mutant plants compared to wild type plants. [3] These methods and discoveries were published in and featured on the cover of Science magazine in February 1995. Millar's luciferase experiments have contributed immensely to the current understanding of the circadian clock in plants. Specifically, Millar's work in 1995 and 2012 have been integral in the development of the repressilator model in plants.

Role of ELF3 and ELF4

With Kay's group, Millar identified roles for the ELF3 and ELF4 genes in the plant circadian system. Plants with loss-of-function mutations in elf3 exhibited arrhythmicity in constant light conditions but not in constant darkness, suggesting that elf3 was necessary for proper control of the clock by light. Additionally, Millar and colleagues showed that ELF3 and its paralog ELF4 are necessary for the proper rhythmic expression of two other important genes involved in the plant circadian clock, Circadian Clock Associated 1 (CCA1) and Late Elongated Hypocotyl (LHY). [4] These early efforts greatly contributed to efforts to understand the mechanisms underlying the function of the plant circadian oscillator. ELF3 and ELF4 have been shown to be important mediators of light input into the plant circadian oscillator. [5] The mechanisms underlying the oscillator's function, specifically the full extent of "ELF3" and "ELF4"'s interactions with other parts of the clock, are an active area of research.

Evolutionary biology of plant circadian clocks

In 2005, Millar and his colleagues discovered how plant circadian clocks increase photosynthesis and growth, thereby offering a selective advantage. First, they compared the survivability of wild-type Arabidopsis, which has a circadian period of about 24 hours, when grown in a 20-hour, then 24-hour, and lastly 28-hour light-dark cycle. Then they examined long (28-hour) and short (20-hour) period mutants grown in light-dark cycles that were similar to, or dissimilar from, their endogenous clock periods. In all three strains, leaves contained more chlorophyll when the period of the plant matched that of the environment. Additionally, both short and long period mutants fixed around 40% more carbon when exogenous periods matched their endogenous rhythms, consistent with the hypothesis of circadian resonance. [4] Millar's experiments demonstrated one possible mechanism that has selected for circadian clock function during plant evolution.

Current research

In 2017, Millar and colleagues quantitatively explained and predicted canonical phenotypes of circadian timing in a multicellular, model organism. The research team used metabolic and physiological data to combine and extend mathematical models of rhythmic gene expression, photoperiod-dependent flowering, elongation growth, and starch metabolism within a framework model for Arabidopsis. The model predicted the effect of altered circadian timing upon particular phenotypes in clock-mutant plants. Whole-plant growth rate decreased, which was attributed to altered night-time metabolism of stored starch in addition to altered mobilisation of secondary stores of organic acids. [6]

Positions

Awards

See also

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

The repressilator is a genetic regulatory network consisting of at least one feedback loop with at least three genes, each expressing a protein that represses the next gene in the loop. In biological research, repressilators have been used to build cellular models and understand cell function. There are both artificial and naturally-occurring repressilators. Recently, the naturally-occurring repressilator clock gene circuit in Arabidopsis thaliana and mammalian systems have been studied.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

Timing of CAB expression 1 is a protein that in Arabidopsis thaliana is encoded by the TOC1 gene. TOC1 is also known as two-component response regulator-like APRR1.

Michael Menaker, was an American chronobiology researcher, and was Commonwealth Professor of Biology at University of Virginia. His research focused on circadian rhythmicity of vertebrates, including contributing to an understanding of light input pathways on extra-retinal photoreceptors of non-mammalian vertebrates, discovering a mammalian mutation for circadian rhythmicity, and locating a circadian oscillator in the pineal gland of bird. He wrote almost 200 scientific publications.

Circadian Clock Associated 1 (CCA1) is a gene that is central to the circadian oscillator of angiosperms. It was first identified in Arabidopsis thaliana in 1993. CCA1 interacts with LHY and TOC1 to form the core of the oscillator system. CCA1 expression peaks at dawn. Loss of CCA1 function leads to a shortened period in the expression of many other genes.

Steve A. Kay is a British-born chronobiologist who mainly works in the United States. Dr. Kay has pioneered methods to monitor daily gene expression in real time and characterized circadian gene expression in plants, flies and mammals. In 2014, Steve Kay celebrated 25 years of successful chronobiology research at the Kaylab 25 Symposium, joined by over one hundred researchers with whom he had collaborated with or mentored. Dr. Kay, a member of the National Academy of Sciences, U.S.A., briefly served as president of The Scripps Research Institute. and is currently a professor at the University of Southern California. He also served on the Life Sciences jury for the Infosys Prize in 2011.

LUX or Phytoclock1 (PCL1) is a gene that codes for LUX ARRHYTHMO, a protein necessary for circadian rhythms in Arabidopsis thaliana. LUX protein associates with Early Flowering 3 (ELF3) and Early Flowering 4 (ELF4) to form the Evening Complex (EC), a core component of the Arabidopsis repressilator model of the plant circadian clock. The LUX protein functions as a transcription factor that negatively regulates Pseudo-Response Regulator 9 (PRR9), a core gene of the Midday Complex, another component of the Arabidopsis repressilator model. LUX is also associated with circadian control of hypocotyl growth factor genes PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PHYTOCHROME INTERACTING FACTOR 5 (PIF5).

Paul Hardin is an American scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

Jennifer Loros, also known as J.J. Loros, is a chronobiologist leading the field in the study of circadian rhythms in Neurospora. Her research focuses on circadian oscillators and their control of gene expression in living cells. Currently, Loros is a professor of Biochemistry, Cell Biology, and Molecular and Systems Biology at the Giesel School of Medicine.

Pseudo-response regulator (PRR) refers to a group of genes that regulate the circadian oscillator in plants. There are four primary PRR proteins that perform the majority of interactions with other proteins within the circadian oscillator, and another (PRR3) that has limited function. These genes are all paralogs of each other, and all repress the transcription of Circadian Clock Associated 1 (CCA1) and Late Elongated Hypocotyl (LHY) at various times throughout the day. The expression of PRR9, PRR7, PRR5 and TOC1/PRR1 peak around morning, mid-day, afternoon and evening, respectively. As a group, these genes are one part of the three-part repressilator system that governs the biological clock in plants.

The Late Elongated Hypocotyl gene (LHY), is an oscillating gene found in plants that functions as part of their circadian clock. LHY encodes components of mutually regulatory negative feedback loops with Circadian Clock Associated 1 (CCA1) in which overexpression of either results in dampening of both of their expression. This negative feedback loop affects the rhythmicity of multiple outputs creating a daytime protein complex. LHY was one of the first genes identified in the plant clock, along with TOC1 and CCA1. LHY and CCA1 have similar patterns of expression, which is capable of being induced by light. Single loss-of-function mutants in both genes result in seemingly identical phenotypes, but LHY cannot fully rescue the rhythm when CCA1 is absent, indicating that they may only be partially functionally redundant. Under constant light conditions, CCA1 and LHY double loss-of-function mutants fail to maintain rhythms in clock-controlled RNAs.

Jay Dunlap is an American chronobiologist and photobiologist who has made significant contributions to the field of chronobiology by investigating the underlying mechanisms of circadian systems in Neurospora, a fungus commonly used as a model organism in biology, and in mice and mammalian cell culture models. Major contributions by Jay Dunlap include his work investigating the role of frq and wc clock genes in circadian rhythmicity, and his leadership in coordinating the whole genome knockout collection for Neurospora. He is currently the Nathan Smith Professor of Molecular and Systems Biology at the Geisel School of Medicine at Dartmouth. He and his colleague Jennifer Loros have mentored numerous students and postdoctoral fellows, many of whom presently hold positions at various academic institutions.

Dmitri Nusinow is an American chronobiologist who studies plant circadian rhythms. He was born on November 7, 1976, in Inglewood, California. He currently resides in St. Louis, and his research focus includes a combination of molecular, biochemical, genetic, genomic, and proteomic tools to discover the molecular connections between signaling networks, circadian oscillators, and specific outputs. By combining these methods, he hopes to apply the knowledge elucidated from the Arabidopsis model to other plant species.

<span class="mw-page-title-main">Sato Honma</span>

Sato Honma is a Japanese chronobiologist who researches the biological mechanisms of circadian rhythms. She mainly collaborates with Ken-Ichi Honma on publications, and both of their primary research focuses are the human circadian clock under temporal isolation and the mammalian suprachiasmatic nucleus (SCN), its components, and associates. Honma is a retired professor at the Hokkaido University School of Medicine in Sapporo, Japan. She received her Ph.D. in physiology from Hokkaido University. She taught physiology at the School of Medicine and then at the Research and Education Center for Brain Science at Hokkaido University. She is currently the director at the Center for Sleep and Circadian Rhythm Disorders at Sapporo Hanazono Hospital and works as a somnologist.

EARLY FLOWERING 3 (ELF3) is a plant-specific gene that encodes the hydroxyproline-rich glycoprotein and is required for the function of the circadian clock. ELF3 is one of the three components that make up the Evening Complex (EC) within the plant circadian clock, in which all three components reach peak gene expression and protein levels at dusk. ELF3 serves as a scaffold to bind EARLY FLOWERING 4 (ELF4) and LUX ARRHYTHMO (LUX), two other components of the EC, and functions to control photoperiod sensitivity in plants. ELF3 also plays an important role in temperature and light input within plants for circadian clock entrainment. Additionally, it plays roles in light and temperature signaling that are independent from its role in the EC.

Elaine Munsey Tobin is a professor of molecular, cell, and developmental biology at the University of California, Los Angeles (UCLA). Tobin is recognized as a Pioneer Member of the American Society of Plant Biologists (ASPB).

Professor Alex A.R. Webb is a plant biologist whose computational, genetic, and physiological studies center around plant chronobiology. He currently serves as the head of the Circadian Signal Transduction Group in the University of Cambridge's Department of Plant Sciences researching circadian pathways and what regulates them.

The chlorophyll a/b-binding protein gene, otherwise known as the CAB gene, is one of the most thoroughly characterized clock-regulated genes in plants. There are a variety of CAB proteins that are derived from this gene family. Studies on Arabidopsis plants have shed light on the mechanisms of biological clocks under the regulation of CAB genes. Dr. Steve Kay discovered that CAB was regulated by a circadian clock, which switched the gene on in the morning and off in the late afternoon. The genes code for proteins that associate with chlorophyll and xanthophylls. This association aids the absorption of sunlight, which transfers energy to photosystem II to drive photosynthetic electron transport.

Stacey Harmer is a chronobiologist whose work centers on the study of circadian rhythms in plants. Her research focuses on the molecular workings of the plant circadian clock and its influences on plant behaviors and physiology. She is a professor in the Department of Plant Biology at the University of California, Davis.

References

  1. University of Edinburgh profile.
  2. Innogen profile Archived 13 April 2017 at the Wayback Machine .
  3. W. Huang, "Mapping the core of the Arabidopsis circadian clock defines the network structure of the oscillator", Science, 2012, PMID   22403178.
  4. 1 2 C. McClung, "Plant Circadian Rhythms", The Plant Cell, 2006, PMC   1425852
  5. M. Nohales and S. A. Kay, "Molecular mechanisms at the core of the plant circadian oscillator", Nature Structural and Molecular Biology, 2016, PMID   27922614
  6. Chew, Yin Hoon; Seaton, Daniel D.; Mengin, Virginie; Flis, Anna; Mugford, Sam T.; Smith, Alison M.; Stitt, Mark; Millar, Andrew J. (6 February 2017). "Linking circadian time to growth rate quantitatively via carbon metabolism". bioRxiv   10.1101/105437 .
  7. EMBO profile.
  8. Royal Society profile.
  9. Royal Society of Edinburgh profile.