Aging Biology Group – Complexbiology Laboratory

nam1

Prof. Nam, Hong Gil

Professor, DGIST Fellow, Director, Institute for Basic Science

University of North Carolina, Chapel Hill, PhD.

Phone: +82-53-785-1800

Email: nam@dgist.ac.kr

Aging Biology Group Homepage

 

Overview

Complex biology is a new paradigm in biology; many of biological phenomena can be understood as emergent properties and behaviors that arise from the biological complex system. Complex biology research group is striving to understand how complex webs of direct and indirect interactions of various molecules such as DNA, RNA, proteins, and small molecules (metabolites, lipids) have developed, how the interactions are performed in the cell, and how the spatial and temporal interactions underlie the emergent biological processes. At higher levels, we are also questioning how cells, organs, and organisms are interacting to form the biological complex system

The researches in the complex biology group are composed of the following five subjects 1) life history, aging, senescence and death in plants, 2) aging and anti-aging in animals and human, 3) light signaling and circadian system, 4) exploratory subjects including intercellular molecular dynamics, origin of life, and quantum biology, and 5) space farm projects.

One of the major questions in our group is how time is incorporated into aging process along lifespan and how aging process is regulated at a systems level. Arabidopsis thaliana has been one of our model systems to understand how plants know when and how to die. Toward understanding the temporal-spatial dynamics of functional and regulatory transitions throughout life history, we are employing systems level analyses including genomics and phenomics in Arabidopsis. One of our new technological challenges is the integration of phenome with other -omics data along lifespan and its application in understanding the evolutionary mechanism of aging and senescence. Senescence and death is in part systemically controlled at the organismal level. We are employing rice as a model system to understand the mechanism underlying the systemic senescence. We are also studying interaction of the two plant timing mechanisms, aging and circadian clock.

Complex biology research group is extending our aging research into animal aging to reveal the time-dependent changes of spatial, temporal molecular and informational webs along the aging process of animal system including mice and worms.

nam2

Research Summary

1. Plant Life History, Aging, and Senescence:

Plant senescence and the concomitant death are among the most dramatic developmental events we encounter in nature, as we observe during whole plant death of several crop plants and during the death process of autumn leaves. Plant senescence and death have a biological “purpose”. Plants accumulate nutrients during the growth phase through carbon fixation and, at the senescence stage, relocate the nutrients to other organs such as developing seeds as a part of the parental investment. Thus, senescence and death in plants are evolutionarily acquired developmental strategies for better fitness. The senescence process is also critically important for humanity: Plants are the primary source of food on earth and the senescence process involving the disassembly and relocation of the nutrients is responsible for production of many important foods such as rice, corn, and wheat, etc. In fact, what we eat mostly are nutrients primarily derived from senescing leaves of crop plants. As the senescence process is critical for fitness of plants, when to die and how to die are under intricate genetic program integrating information on age of plants and organs as well as on environmental and endogenous effectors.

Our overall goal is to gain insights into system-level understanding of senescence and cell death processes in plants from the aspect of life history strategy at molecular, cellular, intercellular, organ and organismal levels and thereby to obtain breakthrough knowledge to improve plant productivity.

Specific Research Aims

  • Identification of spatio-temporal network dynamics with finding of key regulatory modules during life history and senescence
  • Identification of key molecular and cellular mechanisms regulating senescence and death in the context of life history strategy
  • Understanding interaction of endogenous and exogenous signals with life history and senescence
  • Understanding evolution of senescence and death in plants

Research Contents

A. Temporal dynamics of molecular networks along life history and senescence

Aging and senescence are induced by an extensive range of developmental and environmental signals and controlled by multiple, cross-linking pathways. Elucidation of this complex process requires the systems-level view of molecular networks and network modules, overcoming the current, individual component-based view. Furthermore, aging and senescence are not static, but dynamic process, which are regulated by temporal changes of molecular networks for the functional and regulatory transition of cells, organs, and organisms. Thus, identification of the multilayered networks and key modules encoding senescence processes throughout life history will be a crucial next step toward better understanding of senescence and death processes.

  • Network dynamics along life history and senescence: System-level understanding the integrated network for multi-gene family underlying aging
  • Regulatory modules associated with life history and senescence: Understanding evolutional principles of functional network modules to increase adaptability of a system and to allow rapid/robust informational flow through the network/li>
  • Functional and regulatory transition along life history and senescence: Studying how the NAC transcriptional factor networks are shifting along the life span and how the network transition controls aging process/li>

nam3

B. Dynamics of nuclear architecture along leaf aging

The organization of chromatin in the nucleus is important for transcription coordination required for many biological functions both in animals and plants. It has been broadly accepted that the packing of chromatin in the nucleus is not random but structured at several hierarchical levels. During leaf aging, epigenetic change of chromatin including de-condensation of heterochromatin and histone modification occurs in the nuclei. We hypothesize that topological changes of chromatin take place in a regular and orderly pattern, resulting in transition of developmental program along leaf aging. Thus, we will investigate how topological properties of chromatin are involved in reprogramming of transcriptional regulation along leaf aging.

  • Identification of structural modules at chromatin level in Arabidopsis
  • Investigation of topological changes in chromatin on transcriptional coordination during leaf aging
  • Identification of regulatory elements involved in transition of chromatin structural modules during leaf aging

nam4

C. The circadian clock and aging networks

The circadian clock is a time keeping mechanisms of various processes about 24 hours in living organisms in accordance with the rotation of the Earth. A typical example of the existence of circadian clock is jet lag when we travel across multiple longitudes. In plants, many of molecular and physiological responses are also regulated by endogenous circadian clock. The circadian clock is composed of inputs, core oscillators, and outputs. The inputs recognize daily changes in environment such as light and temperature, and entrain the core oscillators. The core oscillators generate and keep their rhythms around 24 hours of period even under constant conditions after the entrainment. These rhythms are translated into output activities in molecular and physiological responses. The plant circadian clock helps living organisms to prepare time-dependent processes in advance, increasing their fitness in many aspects for their entire lifespan.

Circadian clock, life history, and aging are all time-dependent biological events. One of our long-standing questions was if these time-dependent events have any interactive relationships. Our previous result showed that circadian periods of the core oscillator genes are shortened upon aging, revealing the possible relationship of circadian clock with age-dependent developmental processes. The question remains whether the circadian clock controls age-dependent senescence, senescence affects the circadian clock, or they affect each other. We have already found that several components in the circadian and senescence networks show protein-protein interactions. We are currently investigating these interactions and their effects on life history, and senescence.

  • Understanding how the two plant timing events, aging and circadian clock, are interlinked
  • Identification of circadian clock components affecting senescence

nam5

D. Natural adaptation contributed by lifespan-controlling programs

Lifespan controlling programs in plants increase their fitness in local habitats by adjusting their programs to changing environments and their effective strategies have been incorporated into their genome. Their cumulative reciprocal interaction can generate diverse and distinct lifespan controlling programs in ecotypes. Here, we aim to understand how lifespan controlling programs contribute micro-evolution or fitness of ecotypes in their surrounding environments.

  • Investigation of association among phenomic responses, lifespan, and various environmental cues in various accessions through PHI (Plant High-throughput Investigator) system
  • Identification of genetic elements and their natural alleles for lifespan controlling programs through genome-wide association study (GWAS)
  • Dissection of molecular networks in accessions with distinct lifespan history

nam6

E. Senescence/aging in rice

One of our interests is the aging process of leaf organs and its relation with whole plant aging and death. As a model system to understand the mechanism underlying the systemic senescence, we are employing rice that shows a clear systemic aging at the whole plant level. Our recent study of aging in rice also reveals that nutrient relocation is an important process during aging.
Crop productivity relies heavily on nitrogen (N) fertilization. Therefore, increasing plant N use efficiency (NUE) is critical for the development of sustainable agriculture. Plant NUE is inherently influenced by complex processes including N uptake, translocation, assimilation, and remobilization. Increasing both the grain and N harvest index to drive N acquisition and utilization are important approaches for breeding future high-NUE cultivars.

  • Understanding the systemic aging in rice
  • Investigation of the relationship between aging/senescence, environment, and productivity
  • Unraveling the regulatory mechanism that control the nitrogen partitioning in rice for enhancing nitrogen use efficiency

nam7

2. Aging and anti-aging in animals and human

We use comparative animal model systems to gain a better idea of how aging has evolved among different organisms. We are particularly interested in understanding changes in communication between key regulatory molecules, cell to cell interaction, tissue to tissue communication that might contribute to progression of animal aging process in time and space dependent manner.
In mouse, hypothalamus is a part of brain that controls energy metabolism, sexual activity and circadian rhythm through modulation of hormone release in vertebrates. Pancreatic islet is another important organ that controls glucose metabolism through insulin hormone secretion from β cells. Its communication with hypothalamus through hormonal regulation is a key mechanism that provides concerted coordination of metabolism control in mammals. C. elegans is an excellent model system for studying aging process due to short lifespan of 3 weeks and well-studied genetics. Identification of new components that could extend the lifespan of worm would shed light to aging controlling mechanisms applicable to other organisms.
N. furzeri, a short-lived fish, is considered as another promising aging model system. Relatively shorter lifespan of N. furzeri (3 to 6 months) and close resemblance to physiological changes along aging with that of the mammalian aging makes it a desirable organism for aging research. However, this upcoming organism needs quantitative analysis in aging process for stable use

nam8

Specific Research Aims

  • Understanding mechanism of age-dependent functional change in terms of spatial and temporal network dynamics in mouse hypothalamus, hippocampus, and pancreatic islets
  • Identification of key regulatory molecules (microRNA, proteins, metabolites) that cause age dependent decline of memory, digestive system, physical strength, and glucose metabolism
  • Phenome-based aging study
  • RNA biology in aging using C. elegans
  • DNA homeostasis and aging in N. furzeri as a vertebrate model organism

Research Contents

A. Mouse

[Hippocampus and Hypothalamus]
In mouse, hippocampus plays a role in consolidation of short term memory to long term memory and shows highly sensitive, functional decrease in response to aging. Hypothalamus is a part of brain that controls energy metabolism, sexual activity and circadian rhythm through modulation of hormone release in vertebrates. We aim to reveal key molecules and networks that cause aging and age-dependent functional decline of brain.

  • Identification of key neuronal microRNAs that regulate learning and memory aging through modulation of synaptic plasticity controlling genes in hippocampus.
  • Understanding mechanism by which hypothalamus controls energy metabolism in age dependent manner.

nam9

[Islets]

Pancreatic islets are important organ that controls glucose metabolism through insulin secretion from β-cells. Age-dependent impairment of islet function increases the risk for metabolic diseases, type 2 diabetes. However, the mechanism and major causes of the age-dependent decline of islet function are still disputed. We found that the functional properties of beta cells in humans, as well as in mice, change little as the adult organism ages. Instead, blood-borne factors, low-grade chronic inflammation, and other factors affecting vascular function may represent larger threats to islet health and glucose homeostasis.

  • Investigation of age-dependent loss of islets function: inflammation and fibrosis of islet blood vessels
  • Identification of blood-born factors that regulates islets reassembly during aging.
  • What causes dis-functioning of cellular assembly in islets along aging

nam10

B. C. elegans

C. elegans is an excellent model system for studying aging process due to short lifespan of 3 weeks and well-studied genetics. We are exploring novel RNA-regulatory mechanisms involved in the aging process of C. elegans. Aging is tightly associated with decline of physical health status. Maintenance of physical health status during aging is an emerging subject in aging study. We are exploring the causative regulatory pathways for the age-associated physical decline. Identification of new components that could extend the healthspan of worm would shed light to aging controlling mechanisms applicable to other organisms.

nam11

  • Functional study of small RNAs in controlling lifespan
  • Identification of physical health marker
  • Understanding molecular mechanism in physical health decline along aging
  • RNA homeostasis and aging

3. light signaling and circadian system

Many organisms have developed various strategies for perceiving and processing environmental light information to optimize their growth, development, and behavior. Plants, being photosynthetic and sessile, exhibit particularly plastic development and growth, depending on the environmental light information. The quality, intensity, duration, and direction of the environmental light provide plants with information not only on the ambient light condition but also on other elements in their environments such as neighboring plants and seasonal changes. Thus, plants possess a sophisticated light sensing and signaling system that ensures optimal photoperception and responses to their ever-changing environmental conditions. The light-sensing system in plants includes multiple photoreceptors; the UV-B receptor, the UV-A/blue light receptors, and phytochromes.

nam12
nam13

A current model of the circadian clock in Arabidopsis thaliana

The circadian system forms highly regulated network structures to coordinate cyclic changes of diverse physiological processes. The Arabidopsis circadian oscillator is composed of two major interconnected feedback loops, namely the morning and evening loops. The morning loop contains CCA1/ LHY and PRR 7/9. The evening loop contains several components such as TOC1, GI, ELF 3, ELF4, and LUX, which are linked to the morning loop. The orchestrated action of the oscillator components generates an approximately 24-hour rhythm, and changes in these components can lead to alterations of rhythmic behaviors of the circadian outputs.

In recent studies of our lab, we envisioned that the spatial segregation of molecules into subcellular compartments could certainly provide an important regulatory dimension in the plant circadian system. We reported that the nuclear- and cytosol-localized GI has differential functions in controlling diverse circadian processes and this spatial segregation of GI is necessary for function of the plant circadian clock network. GI defines a spatially-coded I3-FFL with LHY, in which nuclear and cytosolic GI act as positive and negative regulators of the circadian core oscillator, LHY, respectively. This spatial network ensures robustness to external noise and control performance in circadian rhythmicity.

Oscillator components and spatial regulatory mode in circadian clock

nam14

Research Contents

  • Identification of key molecules and mechanisms regulating light signaling and senescence
  • Elucidation of molecular mechanisms of GI in subnuclear compartments
  • Understanding interaction between circadian rhythm and development with life history and senescence

4. Exploratory subjects including intercellular molecular dynamics, origin of life, and quantum biology

A. Photosynthesis

Photosynthesis is an assimilatory biological process for extending carbon chain driven by light as an energy source. The sun light absorbed by plants and photosynthetic bacteria is converted into physicochemical energy and is utilized for synthesizing various organic compounds. Throughout the photosynthesis, photosynthetic organisms have provided fundamental building blocks to the ecological basement of food pyramids and have evolved human civilization in many aspects.
Among various energy source in the ancient earth, how does the light become the major source on earth? Although the light itself is abundant in the earth, it is less constant than the chemical energy because of weather and diurnal cycle in the terms of energy consistency. The timeline and the mechanism of the transition of energy usage in organism is still ambiguous, however, Nisbet and Sleep proposed that the ancient photosynthetic apparatus is evolved from photon detection system for IR emitted from hydrothermal vent where the chemical and thermal energy are generated. (Nisbet and Sleep (2001), Nature)
Regarding the energy level of photosynthetically active light, the red and far-red region of the light energy is able to operate the photosynthetic machinery of the oxygenic photosynthetic organisms and near infra-red to that of the most anoxygenic photosynthetic bacteria. Indeed, these region of light can penetrate deeper in the aqueous environments than shorter wavelength light, which is proper choice for the photosynthetic mechanism in early evolutionary step, if the first photosynthetic life formed in such the environment.

nam15

The organisms using NIR as a fuel are mostly the lower photosynthetic bacteria including purple bacteria whose machinery is simpler than the higher plants and cyanobacteria. In addition, the alignment of light absorbing pigment in the light harvesting complex (LH) and the photochemical reaction center (RC) is reversed sometime, suggesting an uphill energy transfer process. Thus, the study about the NIR-utilizing photosynthesis can reveal one of the early histories of life and can track the evolutionary path in the photosynthetic organisms. At the same time, the study can expand the usable light spectrum for the light-driven energy collecting machinery in industrial level.

B. Origin of Life

One of fundamental questions in biology is how the life began, i.e. mechanism of non-living matters such as simple organic compounds turning into self-replicating and self-organizing molecules, protocell, and ultimately into higher living organisms. Several hypotheses for the condition in which the biotic materials such as amino acids, DNA/RNA, peptides, and proteins could be spontaneously synthesized have been speculated and explored. They include deep-sea hypothermal vent, mineral clay, electric spark, ice, etc. One of the key questions for the prebiotic synthesis of biomaterials is how the precursor molecules for the biomaterials could have reached a sufficient concentration such that the synthesis occur and what the energy sources for activating the reaction are. One of the promising hypothesis is that the life was originated from aerosol water droplets. Several arguments and evidences supporting the droplet hypothesis have been reported, including that the droplets provides confined environment for enhancing reaction rates and that water surface plays a catalytic role for chemical reactions.

We have developed a kinetic apparatus which allows mass spectrometric measurement of chemistry in micro-sized liquid droplets. Fast kinetic analysis of protein unfolding and hydrogen-deuterium exchanged at temporal resolution of microseconds was reported. We have also found the chemical reaction rates are accelerated by three orders of magnitude in the microdroplets compared to bulk solution, suggesting the microdroplets provide a preferred environment for promoting chemical reactions. Our goal is to explore prebiotic synthesis of biomaterials in microdroplets. This microdroplet chemistry may provide an insightful platform for shedding light on the question of the origin of life.

nam16
– Understand of the mechanism of life arising from non-living matters
– Spontaneous/enhanced synthesis of biological molecules in microdroplets
– Behaviors of biochemical reactions in microdroplets mimicking the natural environment of cells

C. Molecular dynamics

will be opened soon

5. Space farm

will be opened soon

Selected Publications

  • Almaça J, Molina J, Drigo RA, Abdulreda, Jeon WB, Berggren PO*, Caicedo A*, Nam HG* (2014) Young capillary vessels rejuvenate aged pancreatic islets. PNAS. 111(49): 17612-17617
  • Choi SH, Hyeon DY, Lee IH, Park SJ, Han S, Lee IC, Hwang D*, Nam HG*(2014) Gene duplication of type-B ARR transcription factors systematically extends transcriptional regulatory structures in Arabidopsis. Scientific Reports 4:7197
  • Kim Y, Han S, Yeom M, Kim H, Lim J, Cha JY, Kim WY, Somers D, Putterill J, Nam HG*, Hwang D*. (2013) Balanced Nucleo-cytosolic Partitioning Defines a Spatial Network for Coordination of Circadian Physiology in Plants. Developmental Cell 26(1), 73-85
  • Kim Y, Lim J, Yeom M, Kim H, Kim J, Wang L, Kim WY, Somers D*, Nam HG*. (2013) ELF4 Regulates GIGANTEA Chromatin Access through Subnuclear Sequestration. Cell Reports. 3(3):671-677
  • Kim JH, Woo HR, Kim J, Lim PO, Lee IC, Choi SH, Hwang D, Nam HG*. (2009) Trifurcate feed-forward regulation of age-dependent cell death involving miR164 in Arabidopsis. Science 323(5917): 1053-1057.
  • Kim HJ, Oh SA, Brownfield L, Hong SH, Ryu H, Hwang I, Twell D*, Nam HG*. (2008) Control of plant germline proliferation by SCF(FBL17) degradation of cell cycle inhibitors. Nature 455: 1134-1137.
  • Ryu JS, Kim JI, Kunkel T, Kim BC, Cho DS, Hong SH, Kim SH, Fernandez AP, Kim Y, Alonso JM, Ecker JR, Nagy F, Lim PO, Song PS, Schafer E, Nam HG*. (2005) Phytochrome-specific type 5 phosphatase controls light signal flux by enhancing phytochrome stability and affinity for a signal transducer. Cell 120: 395-406.
  • Park DH, Somers DE, Kim YS, Choy YH, Lim HK, Soh MS, Kim HJ, Kay SA, Nam HG*. (1999) Control of circadian rhythms and photoperiodic flowering by the Arabidopsis GIGANTEA gene. Science 285: 1579-1582.