Publications of Nicolas Buchler    :chronological  alphabetical  combined listing:

%% Papers Published   
   Author = {Hendler, A and Medina, EM and Buchler, NE and de Bruin, RAM and Aharoni,
   Title = {The evolution of a G1/S transcriptional network in
   Journal = {Current Genetics},
   Volume = {64},
   Number = {1},
   Pages = {81-86},
   Year = {2018},
   Month = {February},
   url = {},
   Abstract = {The G1-to-S cell cycle transition is promoted by the
             periodic expression of a large set of genes. In
             Saccharomyces cerevisiae G1/S gene expression is regulated
             by two transcription factor (TF) complexes, the MBF and SBF,
             which bind to specific DNA sequences, the MCB and SCB,
             respectively. Despite extensive research little is known
             regarding the evolution of the G1/S transcription regulation
             including the co-evolution of the DNA binding domains with
             their respective DNA binding sequences. We have recently
             examined the co-evolution of the G1/S TF specificity through
             the systematic generation and examination of chimeric
             Mbp1/Swi4 TFs containing different orthologue DNA binding
             domains in S. cerevisiae (Hendler et al. in PLoS Genet
             13:e1006778. doi: 10.1371/journal.pgen.1006778 , 2017).
             Here, we review the co-evolution of G1/S transcriptional
             network and discuss the evolutionary dynamics and
             specificity of the MBF-MCB and SBF-SCB interactions in
             different fungal species.},
   Doi = {10.1007/s00294-017-0726-3},
   Key = {fds328227}

   Author = {Lin, YT and Buchler, NE},
   Title = {Efficient analysis of stochastic gene dynamics in the
             non-adiabatic regime using piecewise deterministic Markov
   Journal = {Journal of the Royal Society Interface},
   Volume = {15},
   Number = {138},
   Year = {2018},
   Month = {January},
   url = {},
   Abstract = {Single-cell experiments show that gene expression is
             stochastic and bursty, a feature that can emerge from slow
             switching between promoter states with different activities.
             In addition to slow chromatin and/or DNA looping dynamics,
             one source of long-lived promoter states is the slow binding
             and unbinding kinetics of transcription factors to
             promoters, i.e. the non-adiabatic binding regime. Here, we
             introduce a simple analytical framework, known as a
             piecewise deterministic Markov process (PDMP), that
             accurately describes the stochastic dynamics of gene
             expression in the non-adiabatic regime. We illustrate the
             utility of the PDMP on a non-trivial dynamical system by
             analysing the properties of a titration-based oscillator in
             the non-adiabatic limit. We first show how to transform the
             underlying chemical master equation into a PDMP where the
             slow transitions between promoter states are stochastic, but
             whose rates depend upon the faster deterministic dynamics of
             the transcription factors regulated by these promoters. We
             show that the PDMP accurately describes the observed periods
             of stochastic cycles in activator and repressor-based
             titration oscillators. We then generalize our PDMP analysis
             to more complicated versions of titration-based oscillators
             to explain how multiple binding sites lengthen the period
             and improve coherence. Last, we show how noise-induced
             oscillation previously observed in a titration-based
             oscillator arises from non-adiabatic and discrete binding
             events at the promoter site.},
   Doi = {10.1098/rsif.2017.0804},
   Key = {fds332834}

   Author = {Gómez-Schiavon, M and Chen, L-F and West, AE and Buchler,
   Title = {BayFish: Bayesian inference of transcription dynamics from
             population snapshots of single-molecule RNA FISH in single
   Journal = {Genome Biology: biology for the post-genomic
   Volume = {18},
   Number = {1},
   Pages = {164},
   Year = {2017},
   Month = {September},
   url = {},
   Abstract = {Single-molecule RNA fluorescence in situ hybridization
             (smFISH) provides unparalleled resolution in the measurement
             of the abundance and localization of nascent and mature RNA
             transcripts in fixed, single cells. We developed a
             computational pipeline (BayFish) to infer the kinetic
             parameters of gene expression from smFISH data at multiple
             time points after gene induction. Given an underlying model
             of gene expression, BayFish uses a Monte Carlo method to
             estimate the Bayesian posterior probability of the model
             parameters and quantify the parameter uncertainty given the
             observed smFISH data. We tested BayFish on synthetic data
             and smFISH measurements of the neuronal activity-inducible
             gene Npas4 in primary neurons.},
   Doi = {10.1186/s13059-017-1297-9},
   Key = {fds328789}

   Author = {Hendler, A and Medina, EM and Kishkevich, A and Abu-Qarn, M and Klier,
             S and Buchler, NE and de Bruin, RAM and Aharoni, A},
   Title = {Gene duplication and co-evolution of G1/S transcription
             factor specificity in fungi are essential for optimizing
             cell fitness.},
   Journal = {PLoS genetics},
   Volume = {13},
   Number = {5},
   Pages = {e1006778},
   Year = {2017},
   Month = {May},
   url = {},
   Abstract = {Transcriptional regulatory networks play a central role in
             optimizing cell survival. How DNA binding domains and
             cis-regulatory DNA binding sequences have co-evolved to
             allow the expansion of transcriptional networks and how this
             contributes to cellular fitness remains unclear. Here we
             experimentally explore how the complex G1/S transcriptional
             network evolved in the budding yeast Saccharomyces
             cerevisiae by examining different chimeric transcription
             factor (TF) complexes. Over 200 G1/S genes are regulated by
             either one of the two TF complexes, SBF and MBF, which bind
             to specific DNA binding sequences, SCB and MCB,
             respectively. The difference in size and complexity of the
             G1/S transcriptional network across yeast species makes it
             well suited to investigate how TF paralogs (SBF and MBF) and
             DNA binding sequences (SCB and MCB) co-evolved after gene
             duplication to rewire and expand the network of G1/S target
             genes. Our data suggests that whilst SBF is the likely
             ancestral regulatory complex, the ancestral DNA binding
             element is more MCB-like. G1/S network expansion took place
             by both cis- and trans- co-evolutionary changes in closely
             related but distinct regulatory sequences. Replacement of
             the endogenous SBF DNA-binding domain (DBD) with that from
             more distantly related fungi leads to a contraction of the
             SBF-regulated G1/S network in budding yeast, which also
             correlates with increased defects in cell growth, cell size,
             and proliferation.},
   Doi = {10.1371/journal.pgen.1006778},
   Key = {fds326543}

   Author = {Liban, TJ and Medina, EM and Tripathi, S and Sengupta, S and Henry, RW and Buchler, NE and Rubin, SM},
   Title = {Conservation and divergence of C-terminal domain structure
             in the retinoblastoma protein family.},
   Journal = {Proceedings of the National Academy of Sciences of
   Volume = {114},
   Number = {19},
   Pages = {4942-4947},
   Year = {2017},
   Month = {May},
   url = {},
   Abstract = {The retinoblastoma protein (Rb) and the homologous pocket
             proteins p107 and p130 negatively regulate cell
             proliferation by binding and inhibiting members of the E2F
             transcription factor family. The structural features that
             distinguish Rb from other pocket proteins have been unclear
             but are critical for understanding their functional
             diversity and determining why Rb has unique tumor suppressor
             activities. We describe here important differences in how
             the Rb and p107 C-terminal domains (CTDs) associate with the
             coiled-coil and marked-box domains (CMs) of E2Fs. We find
             that although CTD-CM binding is conserved across protein
             families, Rb and p107 CTDs show clear preferences for
             different E2Fs. A crystal structure of the p107 CTD bound to
             E2F5 and its dimer partner DP1 reveals the molecular basis
             for pocket protein-E2F binding specificity and how
             cyclin-dependent kinases differentially regulate pocket
             proteins through CTD phosphorylation. Our structural and
             biochemical data together with phylogenetic analyses of Rb
             and E2F proteins support the conclusion that Rb evolved
             specific structural motifs that confer its unique capacity
             to bind with high affinity those E2Fs that are the most
             potent activators of the cell cycle.},
   Doi = {10.1073/pnas.1619170114},
   Key = {fds326156}

   Author = {Tanouchi, Y and Pai, A and Park, H and Huang, S and Buchler, NE and You,
   Title = {Long-term growth data of Escherichia coli at a single-cell
   Journal = {Scientific Data},
   Volume = {4},
   Pages = {170036},
   Year = {2017},
   Month = {March},
   url = {},
   Abstract = {Long-term, single-cell measurement of bacterial growth is
             extremely valuable information, particularly in the study of
             homeostatic aspects such as cell-size and growth rate
             control. Such measurement has recently become possible due
             to the development of microfluidic technology. Here we
             present data from single-cell measurements of Escherichia
             coli growth over 70 generations obtained for three different
             growth conditions. The data were recorded every minute, and
             contain time course data of cell length and fluorescent
             intensity of constitutively expressed yellow fluorescent
   Doi = {10.1038/sdata.2017.36},
   Key = {fds325578}

   Author = {Medina, EM and Turner, JJ and Gordân, R and Skotheim, JM and Buchler,
   Title = {Punctuated evolution and transitional hybrid network in an
             ancestral cell cycle of fungi.},
   Journal = {eLife},
   Volume = {5},
   Number = {MAY2016},
   Year = {2016},
   Month = {May},
   url = { Duke open
   Abstract = {Although cell cycle control is an ancient, conserved, and
             essential process, some core animal and fungal cell cycle
             regulators share no more sequence identity than
             non-homologous proteins. Here, we show that evolution along
             the fungal lineage was punctuated by the early acquisition
             and entrainment of the SBF transcription factor through
             horizontal gene transfer. Cell cycle evolution in the fungal
             ancestor then proceeded through a hybrid network containing
             both SBF and its ancestral animal counterpart E2F, which is
             still maintained in many basal fungi. We hypothesize that a
             virally-derived SBF may have initially hijacked cell cycle
             control by activating transcription via the cis-regulatory
             elements targeted by the ancestral cell cycle regulator E2F,
             much like extant viral oncogenes. Consistent with this
             hypothesis, we show that SBF can regulate promoters with E2F
             binding sites in budding yeast.},
   Doi = {10.7554/elife.09492},
   Key = {fds315378}

   Author = {Burnetti, AJ and Aydin, M and Buchler, NE},
   Title = {Cell cycle Start is coupled to entry into the yeast
             metabolic cycle across diverse strains and growth
   Journal = {Molecular Biology of the Cell},
   Volume = {27},
   Number = {1},
   Pages = {64-74},
   Year = {2016},
   Month = {January},
   ISSN = {1059-1524},
   url = { Duke open
   Abstract = {Cells have evolved oscillators with different frequencies to
             coordinate periodic processes. Here we studied the
             interaction of two oscillators, the cell division cycle
             (CDC) and the yeast metabolic cycle (YMC), in budding yeast.
             Previous work suggested that the CDC and YMC interact to
             separate high oxygen consumption (HOC) from DNA replication
             to prevent genetic damage. To test this hypothesis, we grew
             diverse strains in chemostat and measured DNA replication
             and oxygen consumption with high temporal resolution at
             different growth rates. Our data showed that HOC is not
             strictly separated from DNA replication; rather, cell cycle
             Start is coupled with the initiation of HOC and catabolism
             of storage carbohydrates. The logic of this YMC-CDC coupling
             may be to ensure that DNA replication and cell division
             occur only when sufficient cellular energy reserves have
             accumulated. Our results also uncovered a quantitative
             relationship between CDC period and YMC period across
             different strains. More generally, our approach shows how
             studies in genetically diverse strains efficiently identify
             robust phenotypes and steer the experimentalist away from
             strain-specific idiosyncrasies.},
   Doi = {10.1091/mbc.e15-07-0454},
   Key = {fds228173}

   Author = {Karapetyan, S and Buchler, NE},
   Title = {Role of DNA binding sites and slow unbinding kinetics in
             titration-based oscillators.},
   Journal = {Physical Review E - Statistical, Nonlinear, and Soft Matter
   Volume = {92},
   Number = {6},
   Pages = {062712},
   Year = {2015},
   Month = {December},
   ISSN = {1539-3755},
   url = { Duke open
   Abstract = {Genetic oscillators, such as circadian clocks, are
             constantly perturbed by molecular noise arising from the
             small number of molecules involved in gene regulation. One
             of the strongest sources of stochasticity is the binary
             noise that arises from the binding of a regulatory protein
             to a promoter in the chromosomal DNA. In this study, we
             focus on two minimal oscillators based on activator
             titration and repressor titration to understand the key
             parameters that are important for oscillations and for
             overcoming binary noise. We show that the rate of unbinding
             from the DNA, despite traditionally being considered a fast
             parameter, needs to be slow to broaden the space of
             oscillatory solutions. The addition of multiple, independent
             DNA binding sites further expands the oscillatory parameter
             space for the repressor-titration oscillator and lengthens
             the period of both oscillators. This effect is a combination
             of increased effective delay of the unbinding kinetics due
             to multiple binding sites and increased promoter
             ultrasensitivity that is specific for repression. We then
             use stochastic simulation to show that multiple binding
             sites increase the coherence of oscillations by mitigating
             the binary noise. Slow values of DNA unbinding rate are also
             effective in alleviating molecular noise due to the
             increased distance from the bifurcation point. Our work
             demonstrates how the number of DNA binding sites and slow
             unbinding kinetics, which are often omitted in biophysical
             models of gene circuits, can have a significant impact on
             the temporal and stochastic dynamics of genetic
   Doi = {10.1103/physreve.92.062712},
   Key = {fds302226}

   Author = {Schaap, P and Barrantes, I and Minx, P and Sasaki, N and Anderson, RW and Bénard, M and Biggar, KK and Buchler, NE and Bundschuh, R and Chen, X and Fronick, C and Fulton, L and Golderer, G and Jahn, N and Knoop, V and Landweber, LF and Maric, C and Miller, D and Noegel, AA and Peace, R and Pierron, G and Sasaki, T and Schallenberg-Rüdinger, M and Schleicher, M and Singh, R and Spaller, T and Storey, KB and Suzuki, T and Tomlinson, C and Tyson, JJ and Warren, WC and Werner, ER and Werner-Felmayer, G and Wilson, RK and Winckler, T and Gott, JM and Glöckner, G and Marwan, W},
   Title = {The Physarum polycephalum Genome Reveals Extensive Use of
             Prokaryotic Two-Component and Metazoan-Type Tyrosine Kinase
   Journal = {Genome Biology and Evolution},
   Volume = {8},
   Number = {1},
   Pages = {109-125},
   Year = {2015},
   Month = {November},
   url = { Duke open
   Abstract = {Physarum polycephalum is a well-studied microbial eukaryote
             with unique experimental attributes relative to other
             experimental model organisms. It has a sophisticated life
             cycle with several distinct stages including amoebal,
             flagellated, and plasmodial cells. It is unusual in
             switching between open and closed mitosis according to
             specific life-cycle stages. Here we present the analysis of
             the genome of this enigmatic and important model organism
             and compare it with closely related species. The genome is
             littered with simple and complex repeats and the coding
             regions are frequently interrupted by introns with a mean
             size of 100 bases. Complemented with extensive transcriptome
             data, we define approximately 31,000 gene loci, providing
             unexpected insights into early eukaryote evolution. We
             describe extensive use of histidine kinase-based
             two-component systems and tyrosine kinase signaling, the
             presence of bacterial and plant type photoreceptors
             (phytochromes, cryptochrome, and phototropin) and of
             plant-type pentatricopeptide repeat proteins, as well as
             metabolic pathways, and a cell cycle control system
             typically found in more complex eukaryotes. Our analysis
             characterizes P. polycephalum as a prototypical eukaryote
             with features attributed to the last common ancestor of
             Amorphea, that is, the Amoebozoa and Opisthokonts.
             Specifically, the presence of tyrosine kinases in
             Acanthamoeba and Physarum as representatives of two
             distantly related subdivisions of Amoebozoa argues against
             the later emergence of tyrosine kinase signaling in the
             opisthokont lineage and also against the acquisition by
             horizontal gene transfer.},
   Doi = {10.1093/gbe/evv237},
   Key = {fds300277}

   Author = {Rienzo, A and Poveda-Huertes, D and Aydin, S and Buchler, NE and Pascual-Ahuir, A and Proft, M},
   Title = {Different Mechanisms Confer Gradual Control and Memory at
             Nutrient- and Stress-Regulated Genes in Yeast.},
   Journal = {Molecular and Cellular Biology},
   Volume = {35},
   Number = {21},
   Pages = {3669-3683},
   Year = {2015},
   Month = {November},
   ISSN = {0270-7306},
   url = { Duke open
   Abstract = {Cells respond to environmental stimuli by fine-tuned
             regulation of gene expression. Here we investigated the
             dose-dependent modulation of gene expression at high
             temporal resolution in response to nutrient and stress
             signals in yeast. The GAL1 activity in cell populations is
             modulated in a well-defined range of galactose
             concentrations, correlating with a dynamic change of histone
             remodeling and RNA polymerase II (RNAPII) association. This
             behavior is the result of a heterogeneous induction delay
             caused by decreasing inducer concentrations across the
             population. Chromatin remodeling appears to be the basis for
             the dynamic GAL1 expression, because mutants with impaired
             histone dynamics show severely truncated dose-response
             profiles. In contrast, the GRE2 promoter operates like a
             rapid off/on switch in response to increasing osmotic
             stress, with almost constant expression rates and
             exclusively temporal regulation of histone remodeling and
             RNAPII occupancy. The Gal3 inducer and the Hog1
             mitogen-activated protein (MAP) kinase seem to determine the
             different dose-response strategies at the two promoters.
             Accordingly, GAL1 becomes highly sensitive and dose
             independent if previously stimulated because of residual
             Gal3 levels, whereas GRE2 expression diminishes upon
             repeated stimulation due to acquired stress resistance. Our
             analysis reveals important differences in the way dynamic
             signals create dose-sensitive gene expression
   Doi = {10.1128/mcb.00729-15},
   Key = {fds228174}

   Author = {Zhou, M and Wang, W and Karapetyan, S and Mwimba, M and Marqués, J and Buchler, NE and Dong, X},
   Title = {Redox rhythm reinforces the circadian clock to gate immune
   Journal = {Nature},
   Volume = {523},
   Number = {7561},
   Pages = {472-476},
   Year = {2015},
   Month = {July},
   ISSN = {0028-0836},
   url = { Duke open
   Abstract = {Recent studies have shown that in addition to the
             transcriptional circadian clock, many organisms, including
             Arabidopsis, have a circadian redox rhythm driven by the
             organism's metabolic activities. It has been hypothesized
             that the redox rhythm is linked to the circadian clock, but
             the mechanism and the biological significance of this link
             have only begun to be investigated. Here we report that the
             master immune regulator NPR1 (non-expressor of
             pathogenesis-related gene 1) of Arabidopsis is a sensor of
             the plant's redox state and regulates transcription of core
             circadian clock genes even in the absence of pathogen
             challenge. Surprisingly, acute perturbation in the redox
             status triggered by the immune signal salicylic acid does
             not compromise the circadian clock but rather leads to its
             reinforcement. Mathematical modelling and subsequent
             experiments show that NPR1 reinforces the circadian clock
             without changing the period by regulating both the morning
             and the evening clock genes. This balanced network
             architecture helps plants gate their immune responses
             towards the morning and minimize costs on growth at night.
             Our study demonstrates how a sensitive redox rhythm
             interacts with a robust circadian clock to ensure proper
             responsiveness to environmental stimuli without compromising
             fitness of the organism.},
   Language = {ENG},
   Doi = {10.1038/nature14449},
   Key = {fds228175}

   Author = {Tanouchi, Y and Pai, A and Park, H and Huang, S and Stamatov, R and Buchler, NE and You, L},
   Title = {A noisy linear map underlies oscillations in cell size and
             gene expression in bacteria.},
   Journal = {Nature},
   Volume = {523},
   Number = {7560},
   Pages = {357-360},
   Year = {2015},
   Month = {July},
   ISSN = {0028-0836},
   url = { Duke open
   Abstract = {During bacterial growth, a cell approximately doubles in
             size before division, after which it splits into two
             daughter cells. This process is subjected to the inherent
             perturbations of cellular noise and thus requires regulation
             for cell-size homeostasis. The mechanisms underlying the
             control and dynamics of cell size remain poorly understood
             owing to the difficulty in sizing individual bacteria over
             long periods of time in a high-throughput manner. Here we
             measure and analyse long-term, single-cell growth and
             division across different Escherichia coli strains and
             growth conditions. We show that a subset of cells in a
             population exhibit transient oscillations in cell size with
             periods that stretch across several (more than ten)
             generations. Our analysis reveals that a simple law
             governing cell-size control-a noisy linear map-explains the
             origins of these cell-size oscillations across all strains.
             This noisy linear map implements a negative feedback on
             cell-size control: a cell with a larger initial size tends
             to divide earlier, whereas one with a smaller initial size
             tends to divide later. Combining simulations of cell growth
             and division with experimental data, we demonstrate that
             this noisy linear map generates transient oscillations, not
             just in cell size, but also in constitutive gene expression.
             Our work provides new insights into the dynamics of
             bacterial cell-size regulation with implications for the
             physiological processes involved.},
   Language = {ENG},
   Doi = {10.1038/nature14562},
   Key = {fds228176}

   Author = {Mazo-Vargas, A and Park, H and Aydin, M and Buchler,
   Title = {Measuring fast gene dynamics in single cells with time-lapse
             luminescence microscopy.},
   Journal = {Molecular Biology of the Cell},
   Volume = {25},
   Number = {22},
   Pages = {3699-3708},
   Year = {2014},
   Month = {November},
   ISSN = {1059-1524},
   url = { Duke open
   Keywords = {Animals • Beetles • Cell Cycle • Cell Cycle
             Proteins • Fireflies • Gene Expression Regulation,
             Fungal* • Insect Proteins • Luciferases •
             Luminescent Measurements • Microfluidic Analytical
             Techniques • Microscopy, Fluorescence •
             Saccharomyces cerevisiae • Saccharomyces cerevisiae
             Proteins • Single-Cell Analysis • Time-Lapse
             Imaging • chemistry • enzymology • genetics
             • genetics* • metabolism •
   Abstract = {Time-lapse fluorescence microscopy is an important tool for
             measuring in vivo gene dynamics in single cells. However,
             fluorescent proteins are limited by slow chromophore
             maturation times and the cellular autofluorescence or
             phototoxicity that arises from light excitation. An
             alternative is luciferase, an enzyme that emits photons and
             is active upon folding. The photon flux per luciferase is
             significantly lower than that for fluorescent proteins. Thus
             time-lapse luminescence microscopy has been successfully
             used to track gene dynamics only in larger organisms and for
             slower processes, for which more total photons can be
             collected in one exposure. Here we tested green, yellow, and
             red beetle luciferases and optimized substrate conditions
             for in vivo luminescence. By combining time-lapse
             luminescence microscopy with a microfluidic device, we
             tracked the dynamics of cell cycle genes in single yeast
             with subminute exposure times over many generations. Our
             method was faster and in cells with much smaller volumes
             than previous work. Fluorescence of an optimized reporter
             (Venus) lagged luminescence by 15-20 min, which is
             consistent with its known rate of chromophore maturation in
             yeast. Our work demonstrates that luciferases are better
             than fluorescent proteins at faithfully tracking the
             underlying gene expression.},
   Language = {eng},
   Doi = {10.1091/mbc.e14-07-1187},
   Key = {fds228177}

   Author = {Tanouchi, Y and Pai, A and Buchler, NE and You, L},
   Title = {Programming stress-induced altruistic death in engineered
   Journal = {Molecular systems biology},
   Volume = {8},
   Pages = {626},
   Year = {2012},
   ISSN = {1744-4292},
   url = {},
   Keywords = {Apoptosis* • Escherichia coli • Genetic
             Engineering* • Microbial Viability* • Models,
             Biological • Reproducibility of Results • Stress,
             Physiological* • cytology* • growth &
   Abstract = {Programmed death is often associated with a bacterial stress
             response. This behavior appears paradoxical, as it offers no
             benefit to the individual. This paradox can be explained if
             the death is 'altruistic': the killing of some cells can
             benefit the survivors through release of 'public goods'.
             However, the conditions where bacterial programmed death
             becomes advantageous have not been unambiguously
             demonstrated experimentally. Here, we determined such
             conditions by engineering tunable, stress-induced altruistic
             death in the bacterium Escherichia coli. Using a
             mathematical model, we predicted the existence of an optimal
             programmed death rate that maximizes population growth under
             stress. We further predicted that altruistic death could
             generate the 'Eagle effect', a counter-intuitive phenomenon
             where bacteria appear to grow better when treated with
             higher antibiotic concentrations. In support of these
             modeling insights, we experimentally demonstrated both the
             optimality in programmed death rate and the Eagle effect
             using our engineered system. Our findings fill a critical
             conceptual gap in the analysis of the evolution of bacterial
             programmed death, and have implications for a design of
             antibiotic treatment.},
   Language = {eng},
   Doi = {10.1038/msb.2012.57},
   Key = {fds228178}

   Author = {Cross, FR and Buchler, NE and Skotheim, JM},
   Title = {Evolution of networks and sequences in eukaryotic cell cycle
   Journal = {Philosophical Transactions B},
   Volume = {366},
   Number = {1584},
   Pages = {3532-3544},
   Year = {2011},
   ISSN = {0962-8436},
   url = { Duke open
   Keywords = {Amino Acid Sequence • Animals • Cell Cycle
             Checkpoints* • Cell Cycle Proteins • Conserved
             Sequence • Eukaryota • Evolution, Molecular*
             • Mammals • Phylogeny • Plant Cells •
             Plants • Sequence Alignment • Yeasts •
             classification • cytology • cytology* •
             genetics • genetics* • metabolism},
   Abstract = {The molecular networks regulating the G1-S transition in
             budding yeast and mammals are strikingly similar in network
             structure. However, many of the individual proteins
             performing similar network roles appear to have unrelated
             amino acid sequences, suggesting either extremely rapid
             sequence evolution, or true polyphyly of proteins carrying
             out identical network roles. A yeast/mammal comparison
             suggests that network topology, and its associated dynamic
             properties, rather than regulatory proteins themselves may
             be the most important elements conserved through evolution.
             However, recent deep phylogenetic studies show that fungal
             and animal lineages are relatively closely related in the
             opisthokont branch of eukaryotes. The presence in plants of
             cell cycle regulators such as Rb, E2F and cyclins A and D,
             that appear lost in yeast, suggests cell cycle control in
             the last common ancestor of the eukaryotes was implemented
             with this set of regulatory proteins. Forward genetics in
             non-opisthokonts, such as plants or their green algal
             relatives, will provide direct information on cell cycle
             control in these organisms, and may elucidate the
             potentially more complex cell cycle control network of the
             last common eukaryotic ancestor. © 2011 The Royal
   Language = {eng},
   Doi = {10.1098/rstb.2011.0078},
   Key = {fds228179}

   Author = {Buchler, NE and Bai, L},
   Title = {Chromatin: Bind at your own RSC},
   Journal = {Current Biology},
   Volume = {21},
   Number = {6},
   Pages = {R223-R225},
   Year = {2011},
   ISSN = {0960-9822},
   url = { Duke open
   Keywords = {Chromatin • DNA-Binding Proteins • Galactokinase
             • Gene Expression Regulation, Fungal • Nucleosomes
             • Promoter Regions, Genetic • Saccharomyces
             cerevisiae Proteins • Transcription Factors •
             genetics • metabolism • metabolism* •
   Abstract = {Recent work has identified a novel RSC-nucleosome complex
             that both strongly phases flanking nucleosomes and presents
             regulatory sites for ready access. These results challenge
             several widely held views. © 2011 Elsevier Ltd All rights
   Language = {eng},
   Doi = {10.1016/j.cub.2011.01.060},
   Key = {fds228180}

   Author = {Buchler, NE and Cross, FR},
   Title = {Protein sequestration generates a flexible ultrasensitive
             response in a genetic network},
   Journal = {Molecular systems biology},
   Volume = {5},
   Pages = {272},
   Year = {2009},
   ISSN = {1744-4292},
   url = {},
   Keywords = {Basic-Leucine Zipper Transcription Factors • Fungal
             Proteins • Gene Expression Regulation, Fungal •
             Gene Regulatory Networks* • Genes, Dominant •
             Genetic Engineering • Models, Genetic* • Mutation
             • Saccharomycetales • Trans-Activators •
             Transcription, Genetic • genetics • metabolism
             • metabolism* • methods*},
   Abstract = {Ultrasensitive responses are crucial for cellular
             regulation. Protein sequestration, where an active protein
             is bound in an inactive complex by an inhibitor, can
             potentially generate ultrasensitivity. Here, in a synthetic
             genetic circuit in budding yeast, we show that sequestration
             of a basic leucine zipper transcription factor by a
             dominant-negative inhibitor converts a graded
             transcriptional response into a sharply ultrasensitive
             response, with apparent Hill coefficients up to 12. A simple
             quantitative model for this genetic network shows that both
             the threshold and the degree of ultrasensitivity depend upon
             the abundance of the inhibitor, exactly as we observed
             experimentally. The abundance of the inhibitor can be
             altered by simple mutation; thus, ultrasensitive responses
             mediated by protein sequestration are easily tuneable. Gene
             duplication of regulatory homodimers and loss-of-function
             mutations can create dominant negatives that sequester and
             inactivate the original regulator. The generation of
             flexible ultrasensitive responses is an unappreciated
             adaptive advantage that could explain the frequent
             evolutionary emergence of dominant negatives.© 2009 EMBO
             and Macmillan Publishers Limited. All rights
   Language = {eng},
   Doi = {10.1038/msb.2009.30},
   Key = {fds228189}

   Author = {Buchler, NE and Louis, M},
   Title = {Molecular Titration and Ultrasensitivity in Regulatory
   Journal = {Journal of Molecular Biology},
   Volume = {384},
   Number = {5},
   Pages = {1106-1119},
   Year = {2008},
   ISSN = {0022-2836},
   url = {},
   Keywords = {Animals • Bacteria • Dimerization • Gene
             Regulatory Networks* • Kinetics • Models,
             Molecular* • Protein Processing, Post-Translational
             • Saccharomyces cerevisiae • Transcription Factors
             • metabolism},
   Abstract = {Protein sequestration occurs when an active protein is
             sequestered by a repressor into an inactive complex. Using
             mathematical and computational modeling, we show how this
             regulatory mechanism (called "molecular titration") can
             generate ultrasensitive or "all-or-none" responses that are
             equivalent to highly cooperative processes. The
             ultrasensitive nature of the input-output response is mainly
             determined by two parameters: the dimer dissociation
             constant and the repressor concentration. Because in vivo
             concentrations are tunable through a variety of mechanisms,
             molecular titration represents a flexible mechanism for
             generating ultrasensitivity. Using physiological parameters,
             we report how details of in vivo protein degradation affect
             the strength of the ultrasensitivity at steady state. Given
             that developmental systems often transduce signals into
             cell-fate decisions on timescales incompatible with steady
             state, we further examine whether molecular titration can
             produce ultrasensitive responses within physiologically
             relevant time intervals. Using Drosophila somatic sex
             determination as a developmental paradigm, we demonstrate
             that molecular titration can generate ultrasensitivity on
             timescales compatible with most cell-fate decisions. Gene
             duplication followed by loss-of-function mutations can
             create dominant negatives that titrate and compete with the
             original protein. Dominant negatives are abundant in gene
             regulatory circuits, and our results suggest that molecular
             titration might be generating an ultrasensitive response in
             these networks. © 2008 Elsevier Ltd. All rights
   Language = {eng},
   Doi = {10.1016/j.jmb.2008.09.079},
   Key = {fds228188}

   Author = {Fritz, G and Buchler, NE and Hwa, T and Gerland, U},
   Title = {Designing sequential transcription logic: A simple genetic
             circuit for conditional memory},
   Journal = {Systems and Synthetic Biology},
   Volume = {1},
   Number = {2},
   Pages = {89-98},
   Organization = {Institute for Theoretical Physics, Universitat zu Koln,
             Zulpicher Str. 77, Koln, Germany, 50937.},
   Institution = {Institute for Theoretical Physics, Universitat zu Koln,
             Zulpicher Str. 77, Koln, Germany, 50937.},
   Year = {2007},
   ISSN = {1872-5325},
   url = {},
   Abstract = {The ability to learn and respond to recurrent events depends
             on the capacity to remember transient biological signals
             received in the past. Moreover, it may be desirable to
             remember or ignore these transient signals conditioned upon
             other signals that are active at specific points in time or
             in unique environments. Here, we propose a simple genetic
             circuit in bacteria that is capable of conditionally
             memorizing a signal in the form of a transcription factor
             concentration. The circuit behaves similarly to a "data
             latch" in an electronic circuit, i.e. it reads and stores an
             input signal only when conditioned to do so by a "read
             command." Our circuit is of the same size as the well-known
             genetic toggle switch (an unconditional latch) which
             consists of two mutually repressing genes, but is
             complemented with a "regulatory front end" involving protein
             heterodimerization as a simple way to implement conditional
             control. Deterministic and stochastic analysis of the
             circuit dynamics indicate that an experimental
             implementation is feasible based on well-characterized genes
             and proteins. It is not known, to which extent molecular
             networks are able to conditionally store information in
             natural contexts for bacteria. However, our results suggest
             that such sequential logic elements may be readily
             implemented by cells through the combination of existing
             protein-protein interactions and simple transcriptional
             regulation. © 2007 Springer Science + Business Media
   Doi = {10.1007/s11693-007-9006-8},
   Key = {Fritz07}

   Author = {Bintu, L and Buchler, NE and Garcia, HG and Gerland, U and Hwa, T and Kondev, J and Kuhlman, T and Phillips, R},
   Title = {Transcriptional regulation by the numbers:
   Journal = {Current Opinion in Genetics and Development},
   Volume = {15},
   Number = {2},
   Pages = {125-135},
   Organization = {Physics Department, Brandeis University, Waltham, MA 02454,
   Institution = {Physics Department, Brandeis University, Waltham, MA 02454,
   Year = {2005},
   url = {},
   Keywords = {Animals Bacteria/genetics DNA/chemistry *Gene Expression
             Regulation Humans *Models, Theoretical Promoter Regions,
             Genetic/genetics Quantitative Trait Loci *Thermodynamics
             *Transcription, Genetic Transcriptional Activation},
   Abstract = {With the increasing amount of experimental data on gene
             expression and regulation, there is a growing need for
             quantitative models to describe the data and relate them to
             their respective context. Thermodynamic models provide a
             useful framework for the quantitative analysis of bacterial
             transcription regulation. This framework can facilitate the
             quantification of vastly different forms of gene expression
             from several well-characterized bacterial promoters that are
             regulated by one or two species of transcription factors; it
             is useful because it requires only a few parameters. As
             such, it provides a compact description useful for
             higher-level studies (e.g. of genetic networks) without the
             need to invoke the biochemical details of every component.
             Moreover, it can be used to generate hypotheses on the
             likely mechanisms of transcriptional control. © 2005
             Elsevier Ltd. All rights reserved.},
   Doi = {10.1016/j.gde.2005.02.006},
   Key = {Bintu05}

   Author = {Buchler, NE and Gerland, U and Hwa, T},
   Title = {Nonlinear protein degradation and the function of genetic
   Journal = {Proceedings of the National Academy of Sciences of the
             United States of America},
   Volume = {102},
   Number = {27},
   Pages = {9559-9564},
   Organization = {Center for Studies in Physics and Biology, The Rockefeller
             University, New York, NY 10021, USA.},
   Institution = {Center for Studies in Physics and Biology, The Rockefeller
             University, New York, NY 10021, USA.},
   Year = {2005},
   url = {},
   Keywords = {Bacteria/genetics *Gene Expression Regulation *Models,
             Biological Multiprotein Complexes/*metabolism Protein
             Engineering/methods Protein Subunits/*metabolism
             Proteins/*metabolism Transcription Factors/metabolism},
   Abstract = {The functions of most genetic circuits require a sufficient
             degree of cooperativity in the circuit components. Although
             mechanisms of cooperativity have been studied most
             extensively in the context of transcriptional initiation
             control, cooperativity from other processes involved in the
             operation of the circuits can also play important roles. In
             this work, we examine a simple kinetic source of
             cooperativity stemming from the nonlinear degradation of
             multimeric proteins. Ample experimental evidence suggests
             that protein subunits can degrade less rapidly when
             associated in multimeric complexes, an effect we refer to as
             "cooperative stability." For dimeric transcription factors,
             this effect leads to a concentration-dependence in the
             degradation rate because monomers, which are predominant at
             low concentrations, will be more rapidly degraded. Thus,
             cooperative stability can effectively widen the accessible
             range of protein levels in vivo. Through theoretical
             analysis of two exemplary genetic circuits in bacteria, we
             show that such an increased range is important for the
             robust operation of genetic circuits as well as their
             evolvability. Our calculations demonstrate that a few-fold
             difference between the degradation rate of monomers and
             dimers can already enhance the function of these circuits
             substantially. We discuss molecular mechanisms of
             cooperative stability and their occurrence in natural or
             engineered systems. Our results suggest that cooperative
             stability needs to be considered explicitly and
             characterized quantitatively in any systematic experimental
             or theoretical study of gene circuits. © 2005 by The
             National Academy of Sciences of the USA.},
   Doi = {10.1073/pnas.0409553102},
   Key = {Buchler05}

   Author = {Archambault, V and Buchler, NE and Wilmes, GM and Jacobson, MD and Cross, FR},
   Title = {Two-faced cyclins with eyes on the targets},
   Journal = {Cell Cycle},
   Volume = {4},
   Number = {1},
   Pages = {125-130},
   Organization = {Rockefeller University, New York, New York,
   Institution = {Rockefeller University, New York, New York,
   Year = {2005},
   Keywords = {Amino Acid Motifs Amino Acid Sequence Cell
             Cycle/genetics/physiology Cyclin B/chemistry/genetics/*physiology
             Cyclin-Dependent Kinases/genetics/physiology
             Cyclins/genetics/physiology DNA Replication *Gene Expression
             Regulation, Fungal Hydrophobicity Molecular Sequence Data
             Origin Recognition Complex/chemistry/genetics/*physiology
             Protein Structure, Tertiary Saccharomyces
             cerevisiae/genetics/*physiology Saccharomyces cerevisiae
             Proteins/chemistry/genetics/*physiology Signal
   Abstract = {We recently reported that the 'hydrophobic patch' (HP) of
             the Saccharomyces cerevisiae S-phase cyclin Clb5 facilitates
             its interaction with Orco (via its Cy or RXL motif),
             providing a mechanism that helps prevent rereplication from
             individual origins. This is the first finding of a
             biological function for an interaction between a cyclin and
             a cyclin-binding motif (Cy or RXL motif) in a target protein
             in Saccharomyces cerevisiae. It is also the first such
             example involving a B-type cyclin in any organism. Yet, some
             of our observations as well as work from other groups
             suggest that HP-RXL interactions are functionally important
             for cyclin-Cdk signaling to other targets. The evolutionary
             conservation of the HP motif suggests that it allows cyclins
             to carry out important and specialized functions. ©2005
             Landes Bioscience.},
   Key = {Archambault05}

   Author = {Bintu, L and Buchler, NE and Garcia, HG and Gerland, U and Hwa, T and Kondev, J and Phillips, R},
   Title = {Transcriptional regulation by the numbers:
   Journal = {Current Opinion in Genetics and Development},
   Volume = {15},
   Number = {2},
   Pages = {116-124},
   Organization = {Physics Department, Brandeis University, Waltham, MA 02454,
   Institution = {Physics Department, Brandeis University, Waltham, MA 02454,
   Year = {2005},
   url = {},
   Keywords = {*Gene Expression Regulation Humans *Models, Theoretical
             *Thermodynamics *Transcription, Genetic},
   Abstract = {The expression of genes is regularly characterized with
             respect to how much, how fast, when and where. Such
             quantitative data demands quantitative models. Thermodynamic
             models are based on the assumption that the level of gene
             expression is proportional to the equilibrium probability
             that RNA polymerase (RNAP) is bound to the promoter of
             interest. Statistical mechanics provides a framework for
             computing these probabilities. Within this framework,
             interactions of activators, repressors, helper molecules and
             RNAP are described by a single function, the 'regulation
             factor'. This analysis culminates in an expression for the
             probability of RNA polymerase binding at the promoter of
             interest as a function of the number of regulatory proteins
             in the cell. © 2005 Elsevier Ltd. All rights
   Doi = {10.1016/j.gde.2005.02.007},
   Key = {Bintu05a}

   Author = {Buchler, NE and Gerland, U and Hwa, T},
   Title = {On schemes of combinatorial transcription
   Journal = {Proceedings of the National Academy of Sciences of the
             United States of America},
   Volume = {100},
   Number = {9},
   Pages = {5136-5141},
   Organization = {Department of Physics and Center for Theoretical Biological
             Physics, University of California at San Diego, La Jolla, CA
             92093-0319, USA.},
   Institution = {Department of Physics and Center for Theoretical Biological
             Physics, University of California at San Diego, La Jolla, CA
             92093-0319, USA.},
   Year = {2003},
   url = {},
   Keywords = {Bacteria/genetics Models, Genetic *Transcription,
   Abstract = {Cells receive a wide variety of cellular and environmental
             signals, which are often processed combinatorially to
             generate specific genetic responses. Here we explore
             theoretically the potentials and limitations of
             combinatorial signal integration at the level of
             cis-regulatory transcription control. Our analysis suggests
             that many complex transcription-control functions of the
             type encountered in higher eukaryotes are already
             implementable within the much simpler bacterial
             transcription system. Using a quantitative model of
             bacterial transcription and invoking only specific
             protein-DNA interaction and weak glue-like interaction
             between regulatory proteins, we show explicit schemes to
             implement regulatory logic functions of increasing
             complexity by appropriately selecting the strengths and
             arranging the relative positions of the relevant
             protein-binding DNA sequences in the cis-regulatory region.
             The architectures that emerge are naturally modular and
             evolvable. Our results suggest that the transcription
             regulatory apparatus is a "programmable" computing machine,
             belonging formally to the class of Boltzmann machines.
             Crucial to our results is the ability to regulate gene
             expression at a distance. In bacteria, this can be achieved
             for isolated genes via DNA looping controlled by the
             dimerization of DNA-bound proteins. However, if adopted
             extensively in the genome, long-distance interaction can
             cause unintentional intergenic cross talk, a detrimental
             side effect difficult to overcome by the known bacterial
             transcription-regulation systems. This may be a key factor
             limiting the genome-wide adoption of complex transcription
             control in bacteria. Implications of our findings for
             combinatorial transcription control in eukaryotes are
   Doi = {10.1073/pnas.0930314100},
   Key = {Buchler03}

   Author = {Buchler, NEG and Goldstein, RA},
   Title = {Surveying determinants of protein structure designability
             across different energy models and amino-acid alphabets: A
   Journal = {Journal of Chemical Physics},
   Volume = {112},
   Number = {5},
   Pages = {2533-2547},
   Year = {2000},
   Abstract = {A variety of analytical and computational models have been
             proposed to answer the question of why some protein
             structures are more "designable" (i.e., have more sequences
             folding into them) than others. One class of analytical and
             statistical-mechanical models has approached the
             designability problem from a thermodynamic viewpoint. These
             models highlighted specific structural features important
             for increased designability. Furthermore, designability was
             shown to be inherently related to thermodynamically relevant
             energetic measures of protein folding, such as the
             foldability ℱ and energy gap Δ10. However, many of these
             models have been done within a very narrow focus: Namely,
             pair-contact interactions and two-letter amino-acid
             alphabets. Recently, two-letter amino-acid alphabets for
             pair-contact models have been shown to contain designability
             artifacts which disappear for larger-letter amino-acid
             alphabets. In addition, a solvation model was demonstrated
             to give identical designability results to previous
             two-letter amino-acid alphabet pair-contact models. In light
             of these discordant results, this report synthesizes a broad
             consensus regarding the relationship between specific
             structural features, foldability ℱ, energy gap Δ10, and
             structure designability for different energy models
             (pair-contact vs solvation) across a wide range of
             amino-acid alphabets. We also propose a novel measure Zkd
             which is shown to be well correlated to designability.
             Finally, we conclusively demonstrate that two-letter
             amino-acid alphabets for pair-contact models appear to be
             solvation models in disguise. © 2000 American Institute of
   Key = {fds228192}

   Author = {Buchler, NEG and Goldstein, RA},
   Title = {Effect of alphabet size and foldability requirements on
             protein structure designability},
   Journal = {Proteins: Structure, Function and Bioinformatics},
   Volume = {34},
   Number = {1},
   Pages = {113-124},
   Organization = {Biophysics Research Division, Ann Arbor, Michigan,
   Institution = {Biophysics Research Division, Ann Arbor, Michigan,
   Year = {1999},
   ISSN = {0887-3585},
   url = {<113::AID-PROT9>3.0.CO;},
   Keywords = {Amino Acids/*chemistry Kinetics *Models, Statistical Normal
             Distribution Protein Conformation *Protein
   Abstract = {A number of investigators have addressed the issue of why
             certain protein structures are especially common by
             considering structure designability, defined as the number
             of sequences that would successfully fold into any
             particular native structure. One such approach, based on
             foldability, suggested that structures could be classified
             according to their maximum possible foldability and that
             this optimal foldability would be highly correlated with
             structure designability. Other approaches have focused on
             computing the designability of lattice proteins written with
             reduced two- letter amino acid alphabets. These different
             approaches suggested contrasting characteristics of the most
             designable structures. This report compares the
             designability of lattice proteins over a wide range of amino
             acid alphabets and foldability requirements. While all
             alphabets have a wide distribution of protein
             designabilities, the form of the distribution depends on how
             protein 'viability' is defined. Furthermore, under
             increasing foldability requirements, the change in
             designabilities for all alphabets are in good agreement with
             the previous conclusions of the foldability approach. Most
             importantly, it was noticed that those structures that were
             highly designable for the two-letter amino acid alphabets
             are not especially designable with higher-letter
   Doi = {10.1002/(SICI)1097-0134(19990101)34:1<113::AID-PROT9>3.0.CO;},
   Key = {Buchler99}

   Author = {Buchler, NEG and Goldstein, RA},
   Title = {Universal correlation between energy gap and foldability for
             the random energy model and lattice proteins},
   Journal = {Journal of Chemical Physics},
   Volume = {111},
   Number = {14},
   Pages = {6599-6609},
   Year = {1999},
   Abstract = {The random energy model, originally used to analyze the
             physics of spin glasses, has been employed to explore what
             makes a protein a good folder versus a bad folder. In
             earlier work, the ratio of the folding temperature over the
             glass-transition temperature was related to a statistical
             measure of protein energy landscapes denoted as the
             foldability F. It was posited and subsequently established
             by simulation that good folders had larger foldabilities, on
             average, than bad folders. An alternative hypothesis,
             equally verified by protein folding simulations, was that it
             is the energy gap Δ between the native state and the next
             highest energy that distinguishes good folders from bad
             folders. This duality of measures has led to some
             controversy and confusion with little done to reconcile the
             two. In this paper, we revisit the random energy model to
             derive the statistical distributions of the various energy
             gaps and foldability. The resulting joint distribution
             allows us to explicitly demonstrate the positive correlation
             between foldability and energy gap. In addition, we compare
             the results of this analytical theory with a variety of
             lattice models. Our simulations indicate that both the
             individual distributions and the joint distribution of
             foldability and energy gap agree qualitatively well with the
             random energy model. It is argued that the universal
             distribution of and the positive correlation between
             foldability and energy gap, both in lattice proteins and the
             random energy model, is simply a stochastic consequence of
             the "thermodynamic hypothesis." © 1999 American Institute
             of Physics.},
   Key = {fds228191}

   Author = {Buchler, NEG and Zuiderweg, ERP and Wang, H and Goldstein,
   Title = {Protein Heteronuclear NMR Assignments Using Mean-Field
             Simulated Annealing},
   Journal = {Journal of Magnetic Resonance},
   Volume = {125},
   Number = {1},
   Pages = {34-42},
   Organization = {Biophysics Research Division, University of Michigan, Ann
             Arbor 48109-1055, USA.},
   Institution = {Biophysics Research Division, University of Michigan, Ann
             Arbor 48109-1055, USA.},
   Year = {1997},
   Keywords = {Computer Simulation Magnetic Resonance Spectroscopy/*methods
             Molecular Weight Proteins/*chemistry},
   Abstract = {A computational method for the assignment of the NMR spectra
             of larger (21 kDa) proteins using a set of six of the most
             sensitive heteronuclear multidimensional nuclear magnetic
             resonance experiments is described. Connectivity data
             obtained from HNCα, HN (CO) Cα, HN (Cα)Hα, and
             Hα(CαCO)NH and spin-system identification data obtained
             from CP-(H)CCH-TOCSY and CP-(H)C(CαCO)NH-TOCSY were used to
             perform sequence-specific assignments using a mean-field
             formalism and simulated annealing. This mean-field method
             reports the resonance assignments in a probabilistic
             fashion, displaying the certainty of assignments in an
             unambiguous and quantitative manner. This technique was
             applied to the NMR data of the 172-residue peptide-binding
             domain of the E. coli heat-shock protein, DnaK. The method
             is demonstrated to be robust to significant amounts of
             missing, spurious, noisy, extraneous, and erroneous data. ©
             1997 Academic Press.},
   Key = {Buchler97}

   Author = {J. R. Buchler and N. E. Buchler},
   Title = {BL Herculis model pulsations; III. Livermore
   Volume = {285},
   Pages = {213-219},
   Year = {1994},
   Key = {fds161166}