Academic Appointments


Honors & Awards


  • Postdoctoral Fellowship (F32), NIH (2006-2008)
  • Career Award at the Scientific Interface, Burroughs Wellcome Fund (2008)

Professional Education


  • PhD, University of Cambridge, Applied Mathematics (2004)
  • CASM Pt III, University of Cambridge, Applied Mathematics (2001)
  • BS, MIT, Mathematics (1999)
  • BS, MIT, Physics (1999)

Current Research and Scholarly Interests


Underlying the wonderful diversity of natural forms is the ability of an organism to grow into its appropriate shape. Regulation ensures that cells grow, divide and differentiate so that the organism and its constitutive parts are properly proportioned and of suitable size. Although the size-control mechanism active in an individual cell is of fundamental importance to this process, it is difficult to isolate and study in complex multi-cellular systems and remains poorly understood. It is therefore of interest to study size control in unicellular organisms, which are governed by simpler physiology: proliferate rapidly whenever environmental conditions permit. Therefore, the laboratory studies size control in budding yeast, a genetically tractable eukaryotic organism. Previous studies of the budding yeast cell cycle, which couples growth and division, have revealed mechanisms shared by both yeasts and humans. This leads me to believe our findings will be of general interest, particularly since mammalian size control genes are frequently mutated in cancers.

In the 1970s, Lee Hartwell and colleagues attributed size control to a point between cell birth and DNA replication. Upon passage through the size-control checkpoint, budding yeast irreversibly commit to division. This checkpoint was therefore called the Start of the cell cycle. The last 30 years have seen rapid advances in our understanding of the molecular interactions in the cell cycle. Yet, in spite of all this exquisite molecular detail fundamental questions remain unanswered: What makes this transition irreversible? Where in this sequence of molecular interactions does size control occur? How does a cell compute its own size? The laboratory aims to address such systems-level questions.

A central aim of the burgeoning field of systems biology is to understand the principles governing genetic control networks. I believe finding the principles underlying genetic circuits will occur through detailed studies and then comparisons of several natural systems. Due to its extensive development as an experimental system, the budding yeast cell cycle is poised to become central to this enterprise. A systematic understanding of biological control circuits should allow us to more readily discern the function of natural systems and aid us in engineering synthetic systems.

2013-14 Courses


Graduate and Fellowship Programs


Journal Articles


  • Control of cell cycle transcription during G1 and S phases NATURE REVIEWS MOLECULAR CELL BIOLOGY Bertoli, C., Skotheim, J. M., de Bruin, R. A. 2013; 14 (8): 518-528

    Abstract

    The accurate transition from G1 phase of the cell cycle to S phase is crucial for the control of eukaryotic cell proliferation, and its misregulation promotes oncogenesis. During G1 phase, growth-dependent cyclin-dependent kinase (CDK) activity promotes DNA replication and initiates G1-to-S phase transition. CDK activation initiates a positive feedback loop that further increases CDK activity, and this commits the cell to division by inducing genome-wide transcriptional changes. G1-S transcripts encode proteins that regulate downstream cell cycle events. Recent work is beginning to reveal the complex molecular mechanisms that control the temporal order of transcriptional activation and inactivation, determine distinct functional subgroups of genes and link cell cycle-dependent transcription to DNA replication stress in yeast and mammals.

    View details for DOI 10.1038/nrm3629

    View details for Web of Science ID 000322118200013

    View details for PubMedID 23877564

  • Feedforward regulation ensures stability and rapid reversibility of a cellular state. Molecular cell Doncic, A., Skotheim, J. M. 2013; 50 (6): 856-868

    Abstract

    Cellular transitions are important for all life. Such transitions, including cell fate decisions, often employ positive feedback regulation to establish and stabilize new cellular states. However, positive feedback is unlikely to underlie stable cell-cycle arrest in yeast exposed to mating pheromone because the signaling pathway is linear, rather than bistable, over a broad range of extracellular pheromone concentration. We show that the stability of the pheromone-arrested state results from coherent feedforward regulation of the cell-cycle inhibitor Far1. This network motif is effectively isolated from the more complex regulatory network in which it is embedded. Fast regulation of Far1 by phosphorylation allows rapid cell-cycle arrest and reentry, whereas slow Far1 synthesis reinforces arrest. We expect coherent feedforward regulation to be frequently implemented at reversible cellular transitions because this network motif can achieve the ostensibly conflicting aims of arrest stability and rapid reversibility without loss of signaling information.

    View details for DOI 10.1016/j.molcel.2013.04.014

    View details for PubMedID 23685071

  • Cell growth and cell cycle control. Molecular biology of the cell Skotheim, J. M. 2013; 24 (6): 678-?

    View details for DOI 10.1091/mbc.E13-01-0002

    View details for PubMedID 23486402

  • A SHIFT IN THE LONG-TERM MODE OF FORAMINIFERAN SIZE EVOLUTION CAUSED BY THE END-PERMIAN MASS EXTINCTION EVOLUTION Payne, J. L., Jost, A. B., Wang, S. C., Skotheim, J. M. 2013; 67 (3): 816-827

    Abstract

    Size is among the most important traits of any organism, yet the factors that control its evolution remain poorly understood. In this study, we investigate controls on the evolution of organismal size using a newly compiled database of nearly 25,000 foraminiferan species and subspecies spanning the past 400 million years. We find a transition in the pattern of foraminiferan size evolution from correlation with atmospheric pO2 during the Paleozoic (400-250 million years ago) to long-term stasis during the post-Paleozoic (250 million years ago to present). Thus, a dramatic shift in the evolutionary mode coincides with the most severe biotic catastrophe of the Phanerozoic (543 million years ago to present). Paleozoic tracking of pO2 was confined to Order Fusulinida, whereas Paleozoic lagenides, miliolids, and textulariids were best described by the stasis model. Stasis continued to best describe miliolids and textulariids during post-Paleozoic time, whereas random walk was the best supported mode for the other diverse orders. The shift in evolutionary dynamics thus appears to have resulted primarily from the selective elimination of fusulinids at the end of the Permian Period. These findings illustrate the potential for mass extinction to alter macroevolutionary dynamics for hundreds of millions of years.

    View details for DOI 10.1111/j.1558-5646.2012.01807.x

    View details for Web of Science ID 000315894800018

    View details for PubMedID 23461330

  • An algorithm to automate yeast segmentation and tracking. PloS one Doncic, A., Eser, U., Atay, O., Skotheim, J. M. 2013; 8 (3)

    Abstract

    Our understanding of dynamic cellular processes has been greatly enhanced by rapid advances in quantitative fluorescence microscopy. Imaging single cells has emphasized the prevalence of phenomena that can be difficult to infer from population measurements, such as all-or-none cellular decisions, cell-to-cell variability, and oscillations. Examination of these phenomena requires segmenting and tracking individual cells over long periods of time. However, accurate segmentation and tracking of cells is difficult and is often the rate-limiting step in an experimental pipeline. Here, we present an algorithm that accomplishes fully automated segmentation and tracking of budding yeast cells within growing colonies. The algorithm incorporates prior information of yeast-specific traits, such as immobility and growth rate, to segment an image using a set of threshold values rather than one specific optimized threshold. Results from the entire set of thresholds are then used to perform a robust final segmentation.

    View details for DOI 10.1371/journal.pone.0057970

    View details for PubMedID 23520484

  • LATE PALEOZOIC FUSULINOIDEAN GIGANTISM DRIVEN BY ATMOSPHERIC HYPEROXIA EVOLUTION Payne, J. L., Groves, J. R., Jost, A. B., Thienan Nguyen, T., Moffitt, S. E., Hill, T. M., Skotheim, J. M. 2012; 66 (9): 2929-2939

    Abstract

    Atmospheric hyperoxia, with pO(2) in excess of 30%, has long been hypothesized to account for late Paleozoic (360-250 million years ago) gigantism in numerous higher taxa. However, this hypothesis has not been evaluated statistically because comprehensive size data have not been compiled previously at sufficient temporal resolution to permit quantitative analysis. In this study, we test the hyperoxia-gigantism hypothesis by examining the fossil record of fusulinoidean foraminifers, a dramatic example of protistan gigantism with some individuals exceeding 10 cm in length and exceeding their relatives by six orders of magnitude in biovolume. We assembled and examined comprehensive regional and global, species-level datasets containing 270 and 1823 species, respectively. A statistical model of size evolution forced by atmospheric pO(2) is conclusively favored over alternative models based on random walks or a constant tendency toward size increase. Moreover, the ratios of volume to surface area in the largest fusulinoideans are consistent in magnitude and trend with a mathematical model based on oxygen transport limitation. We further validate the hyperoxia-gigantism model through an examination of modern foraminiferal species living along a measured gradient in oxygen concentration. These findings provide the first quantitative confirmation of a direct connection between Paleozoic gigantism and atmospheric hyperoxia.

    View details for DOI 10.1111/j.1558-5646.2012.01626.x

    View details for Web of Science ID 000308405100020

    View details for PubMedID 22946813

  • Cell Size Control in Yeast CURRENT BIOLOGY Turner, J. J., Ewald, J. C., Skotheim, J. M. 2012; 22 (9): R350-R359

    Abstract

    Cell size is an important adaptive trait that influences nearly all aspects of cellular physiology. Despite extensive characterization of the cell-cycle regulatory network, the molecular mechanisms coupling cell growth to division, and thereby controlling cell size, have remained elusive. Recent work in yeast has reinvigorated the size control field and suggested provocative mechanisms for the distinct functions of setting and sensing cell size. Further examination of size-sensing models based on spatial gradients and molecular titration, coupled with elucidation of the pathways responsible for nutrient-modulated target size, may reveal the fundamental principles of eukaryotic cell size control.

    View details for DOI 10.1016/j.cub.2012.02.041

    View details for Web of Science ID 000303967600019

    View details for PubMedID 22575477

  • Evolution of networks and sequences in eukaryotic cell cycle control PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Cross, F. R., Buchler, N. E., Skotheim, J. M. 2011; 366 (1584): 3532-3544

    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.

    View details for DOI 10.1098/rstb.2011.0078

    View details for Web of Science ID 000296981900006

    View details for PubMedID 22084380

  • Commitment to a Cellular Transition Precedes Genome-wide Transcriptional Change MOLECULAR CELL Eser, U., Falleur-Fettig, M., Johnson, A., Skotheim, J. M. 2011; 43 (4): 515-527

    Abstract

    In budding yeast, commitment to cell division corresponds to activating the positive feedback loop of G1 cyclins controlled by the transcription factors SBF and MBF. This pair of transcription factors has over 200 targets, implying that cell-cycle commitment coincides with genome-wide changes in transcription. Here, we find that genes within this regulon have a well-defined distribution of transcriptional activation times. Combinatorial use of SBF and MBF results in a logical OR function for gene expression and partially explains activation timing. Activation of G1 cyclin expression precedes the activation of the bulk of the G1/S regulon, ensuring that commitment to cell division occurs before large-scale changes in transcription. Furthermore, we find similar positive feedback-first regulation in the yeasts S. bayanus and S. cerevisiae, as well as human cells. The widespread use of the feedback-first motif in eukaryotic cell-cycle control, implemented by nonorthologous proteins, suggests its frequent deployment at cellular transitions.

    View details for DOI 10.1016/j.molcel.2011.06.024

    View details for Web of Science ID 000294151000005

    View details for PubMedID 21855792

  • Distinct Interactions Select and Maintain a Specific Cell Fate MOLECULAR CELL Doncic, A., Falleur-Fettig, M., Skotheim, J. M. 2011; 43 (4): 528-539

    Abstract

    The ability to specify and maintain discrete cell fates is essential for development. However, the dynamics underlying selection and stability of distinct cell types remain poorly understood. Here, we provide a quantitative single-cell analysis of commitment dynamics during the mating-mitosis switch in budding yeast. Commitment to division corresponds precisely to activating the G1 cyclin positive feedback loop in competition with the cyclin inhibitor Far1. Cyclin-dependent phosphorylation and inhibition of the mating pathway scaffold Ste5 are required to ensure exclusive expression of the mitotic transcriptional program after cell cycle commitment. Failure to commit exclusively results in coexpression of both cell cycle and pheromone-induced genes, and a morphologically mixed inviable cell fate. Thus, specification and maintenance of a cellular state are performed by distinct interactions, which are likely a consequence of disparate reaction rates and may be a general feature of the interlinked regulatory networks responsible for selecting cell fates.

    View details for DOI 10.1016/j.molcel.2011.06.025

    View details for Web of Science ID 000294151000006

    View details for PubMedID 21855793

  • Cell signaling. To divide or not to divide. Science Skotheim, J. M. 2009; 324 (5926): 476-477

    View details for DOI 10.1126/science.1173769

    View details for PubMedID 19390035

  • Positive feedback of G1 cyclins ensures coherent cell cycle entry NATURE Skotheim, J. M., Di Talia, S., Siggia, E. D., Cross, F. R. 2008; 454 (7202): 291-U12

    Abstract

    In budding yeast, Saccharomyces cerevisiae, the Start checkpoint integrates multiple internal and external signals into an all-or-none decision to enter the cell cycle. Here we show that Start behaves like a switch due to systems-level feedback in the regulatory network. In contrast to current models proposing a linear cascade of Start activation, transcriptional positive feedback of the G1 cyclins Cln1 and Cln2 induces the near-simultaneous expression of the approximately 200-gene G1/S regulon. Nuclear Cln2 drives coherent regulon expression, whereas cytoplasmic Cln2 drives efficient budding. Cells with the CLN1 and CLN2 genes deleted frequently arrest as unbudded cells, incurring a large fluctuation-induced fitness penalty due to both the lack of cytoplasmic Cln2 and insufficient G1/S regulon expression. Thus, positive-feedback-amplified expression of Cln1 and Cln2 simultaneously drives robust budding and rapid, coherent regulon expression. A similar G1/S regulatory network in mammalian cells, comprised of non-orthologous genes, suggests either conservation of regulatory architecture or convergent evolution.

    View details for DOI 10.1038/nature07118

    View details for Web of Science ID 000257665300029

    View details for PubMedID 18633409

  • The effects of molecular noise and size control on variability in the budding yeast cell cycle NATURE Di Talia, S., Skotheim, J. M., Bean, J. M., Siggia, E. D., Cross, F. R. 2007; 448 (7156): 947-U12

    Abstract

    Molecular noise in gene expression can generate substantial variability in protein concentration. However, its effect on the precision of a natural eukaryotic circuit such as the control of cell cycle remains unclear. We use single-cell imaging of fluorescently labelled budding yeast to measure times from division to budding (G1) and from budding to the next division. The variability in G1 decreases with the square root of the ploidy through a 1N/2N/4N ploidy series, consistent with simple stochastic models for molecular noise. Also, increasing the gene dosage of G1 cyclins decreases the variability in G1. A new single-cell reporter for cell protein content allows us to determine the contribution to temporal G1 variability of deterministic size control (that is, smaller cells extending G1). Cell size control contributes significantly to G1 variability in daughter cells but not in mother cells. However, even in daughters, size-independent noise is the largest quantitative contributor to G1 variability. Exit of the transcriptional repressor Whi5 from the nucleus partitions G1 into two temporally uncorrelated and functionally distinct steps. The first step, which depends on the G1 cyclin gene CLN3, corresponds to noisy size control that extends G1 in small daughters, but is of negligible duration in mothers. The second step, whose variability decreases with increasing CLN2 gene dosage, is similar in mothers and daughters. This analysis decomposes the regulatory dynamics of the Start transition into two independent modules, a size sensing module and a timing module, each of which is predominantly controlled by a different G1 cyclin.

    View details for DOI 10.1038/nature06072

    View details for Web of Science ID 000248912900051

    View details for PubMedID 17713537