What the causes of aging are and which factors define lifespan are key questions in the understanding of aging. Here, it is argued that cellular life involves (i) inevitable accumulation of damage resulting from imperfectness and heterogeneity of every cellular process, and (ii) dilution of damage when cells divide. While severe damage is cleared by protective systems, milder damage can only be diluted, due to high cost of accuracy, greater number of damage forms than protective systems, and the constraints inherited from unicellular life. This also applies to cancer cells, which are particularly dependent on damage dilution. Restriction on cell division necessarily leads to aging. Interventions that extend lifespan act through metabolic reprogramming, thereby changing damage composition and the rate of damage accumulation. Thus, heterogeneity leading to the myriad of mild damage forms represents the cause of aging, whereas the processes that affect damage landscape and accumulation are lifespan regulators.
Arsenic and phosphorus are group 15 elements with similar chemical properties. Is it possible that arsenate could replace phosphate in some of the chemicals that are required for life? Phosphate esters are ubiquitous in biomolecules and are essential for life, from the sugar phosphates of intermediary metabolism to ATP to phospholipids to the phosphate backbone of DNA and RNA. Some enzymes that form phosphate esters catalyze the formation of arsenate esters. Arsenate esters hydrolyze very rapidly in aqueous solution, which makes it improbable that phosphorous could be completely replaced with arsenic to support life. Studies of bacterial growth at high arsenic:phosphorus ratios demonstrate that relatively high arsenic concentrations can be tolerated, and that arsenic can become involved in vital functions in the cell, though likely much less efficiently than phosphorus. Recently Wolfe-Simon et al.  reported the isolation of a microorganism that they maintain uses arsenic in place of phosphorus for growth. Here, we examine and evaluate their data and conclusions.
arsenate; arsenic life; ester hydrolysis; phosphate
Planctomycetes, Verrucomicrobia and Chlamydia are prokaryotic phyla that are sometimes grouped together as the PVC superphylum of eubacteria. Some PVC species possess interesting attributes, in particular, internal membranes that superficially resemble eukaryotic endomembranes. Some biologists now claim that PVC bacteria are nucleus-bearing prokaryotes and that they are evolutionary intermediates in the transition from prokaryote to eukaryote. PVC prokaryotes do not possess a nucleus and are not intermediates in the prokaryote-to-eukaryote transition. All of the PVC traits that are currently cited as evidence for aspiring eukaryoticity are either analogous (the result of convergent evolution), not homologous, to eukaryotic traits; or else they are the result of lateral gene transfers. Here we summarize the evidence that shows why most of the purported similarities between the PVC bacteria and eukaryotes are analogous and the rest are consequence of lateral gene acquisition.
Metazoans (multicellular animals) are defined by the presence of polarized epithelial tissues, and epithelial morphogenesis contributes to the diversity of animal body plans. The recent finding of a polarized epithelium in the non-metazoan social amoeba Dictyostelium discoideum demonstrates that an epithelial tissue is not a unique feature of metazoans and calls into question the traditional view that multicellularity evolved independently in social amoebae and metazoans. We propose the alternative hypothesis that animals, fungi and social amoebae evolved from an ancestor that spent a portion of its life cycle in a multicellular state and possessed molecular machinery necessary for forming an epithelial tissue. This hypothesis makes testable predictions regarding tissue organization in close relatives of metazoans and provides a novel conceptual framework for studies of early animal evolution.
Despite its wide existence, the adaptive role of aneuploidy (the abnormal state of having unequal number of different chromosomes) has been a subject of debate. Cellular aneuploidy has been associated with enhanced resistance to stress, whereas on the organismal level it is detrimental to multi-cellular species. Certain aneuploid karyotypes are deleterious for specific environments, but karyotype diversity in a population potentiates adaptive evolution. To reconcile these paradoxical observations, this review distinguishes the role of aneuploidy in cellular versus organismal evolution. Further, it proposes a population genetics perspective to examine the behavior of aneuploidy on a populational versus individual level. By altering the copy number of a significant portion of the genome, aneuploidy introduces large phenotypic leap that enables small cell populations to explore a wide phenotypic landscape, from which adaptive traits can be selected. The production of chromosome number variation can be further increased by stress- or mutation-induced chromosomal instability, fueling rapid cellular adaptation.
We review state-of-the-art computational methods for constructing, from image data, generative statistical models of cellular and nuclear shapes and the arrangement of subcellular structures and proteins within them. These automated approaches allow consistent analysis of images of cells for the purposes of learning the range of possible phenotypes, discriminating between them, and informing further investigation. Such models can also provide realistic geometry and initial protein locations to simulations in order to better understand cellular and subcellular processes. To determine the structures of cellular components and how proteins and other molecules are distributed among them, the generative modeling approach described here can be coupled with high throughput imaging technology to infer and represent subcellular organization from data with few a priori assumptions. We also discuss potential improvements to these methods and future directions for research.
cell modeling; cell shape; generative models; image analysis; machine learning
Recent studies indicate that mammalian chromosomes contain discrete cis-acting loci that control replication timing, mitotic condensation and stability of entire chromosomes. Disruption of the large non-coding RNA gene ASAR6 results in late replication, an under-condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono-allelic expression and asynchronous replication timing. Additional ‘chromosome engineering’ studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain ‘inactivation/stability centers’ that control proper replication, condensation and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types of cis-acting elements, origins, telomeres centromeres, and ‘inactivation/stability centers’, all functioning to ensure proper replication, condensation, segregation and stability of individual chromosomes.
Mixed lineage leukemia (MLL) fusion protein (FP)-induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild-type (WT) MLL, MLL-FPs and other partners such as the chromatin-associated protein LEDGF and the transcription factor c-myb to promote leukemogenesis. The newly solved co-crystal structure illustrating the menin-MLL interaction, coupled with the role of menin in recruiting both WT MLL and MLL-FPs to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL-FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain-containing Brd4-related pathways to sustain MLL-FP-induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL-FP leukemias.
Menin; MLL; Chromatin; Leukemia; Therapy
Activating the ERK pathway (extracellular signal-regulated kinase pathway) has proven beneficial in several models of Huntington’s disease, and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. Huntington’s disease is caused by an expanded polyglutamine repeat in the huntingtin protein that actuates a diverse set of pathogenic mechanisms. In response to mutant huntingtin, ERK is activated and directs a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant huntingtin compromises the ERK dependent transcriptional response to corticostriatal BDNF signaling. Mutant huntingtin also hinders glutamate uptake from the synaptic cleft by down-regulating ERK dependent expression of glutamate transporters leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK which can be protective.
ERK; Huntington’s disease; MAP kinase; neurodegenerative disorders; polyglutamine
Gradual degradation seems inevitable for non-recombining sex chromosomes. This has been supported by the observation of degenerated non-recombining sex chromosomes in a variety of species. The human Y chromosome has also degenerated significantly during its evolution, and theories have been advanced that the Y chromosome could disappear within the next ~5 million years, if the degeneration rate it has experienced continues. However, recent studies suggest that this is unlikely. Conservative evolutionary forces such as strong purifying selection and intrachromosomal repair through gene conversion balance the degeneration tendency of the Y chromosome and maintain its integrity after an initial period of faster degeneration. We discuss the evidence both for and against the extinction of the Y chromosome. We also discuss potential insights gained on the evolution of sex-determining chromosomes by studying simpler sex-determining chromosomal regions of unicellular and multicellular microorganisms.
evolution; sex chromosome; microorganism
Developing cells acquire mature fates in part by selective (i.e. qualitatively different) expression of a few cell-specific genes. However, all cells share the same basic repertoire of molecular and sub-cellular building blocks. Therefore, cells must also specialize according to quantitative differences in cell-specific distributions of those common molecular resources. Here we propose the novel hypothesis that evolutionarily-conserved transcription factors called scaling factors (SFs) regulate quantitative differences among mature cell types. SFs: 1) are induced during late stages of cell maturation; 2) are dedicated to specific sub-cellular domains; and, thus, 3) allow cells to emphasize specific sub-cellular features. We identify candidate SFs and discuss one in detail: MIST1 (BHLHA15, vertebrates)/ DIMM (CG8667, Drosophila); professional secretory cells use this SF to scale up regulated secretion. Because cells use SFs to develop their mature properties and also to adapt them to ever-changing environmental conditions, SF aberrations likely contribute to diseases of adult onset.
differentiation; DIMM; MIST1; sub-cellular domains; transcription factor
Pointillistic approach based super-resolution techniques, such as photoactivated localization microscopy (PALM), involve multiple cycles of sequential activation, imaging and precise localization of single fluorescent molecules. A super-resolution image, having nanoscopic structural information, is then constructed by compiling all the image sequences. Because the final image resolution is determined by the localization precision of detected single molecules and their density, accurate image reconstruction requires imaging of biological structures labeled with fluorescent molecules at high density. In such image datasets, stochastic variations in photon emission and intervening dark states lead to uncertainties in identification of single molecules. This, in turn, prevents the proper utilization of the wealth of information on molecular distribution and quantity. A recent strategy for overcoming this problem is pair-correlation analysis applied to PALM. Using rigorous statistical algorithms to estimate the number of detected proteins, this approach allows the spatial organization of molecules to be quantitatively described.
The discovery and engineering of novel fluorescent proteins (FPs) from diverse organisms is yielding fluorophores with exceptional characteristics for live-cell imaging. In particular, the development of FPs for fluorescence (or Förster) resonance energy transfer (FRET) microscopy is providing important tools for monitoring dynamic protein interactions inside living cells. The increased interest in FRET microscopy has driven the development of many different methods to measure FRET. However, the interpretation of FRET measurements is complicated by several factors including the high fluorescence background, the potential for photoconversion artifacts, and the relatively low dynamic range afforded by this technique. Here, we describe the advantages and disadvantages of four methods commonly used in FRET microscopy. We then discuss the selection of FPs for the different FRET methods, identifying the most useful FP candidates for FRET microscopy. The recent success in expanding the FP color palette offers the opportunity to explore new FRET pairs.
fluorescent protein; fluorescence resonance energy transfer (FRET); fluorescence lifetime imaging microscopy (FLIM); acceptor photobleaching; spectral imaging
Molecular interactions are at the origin of life. How molecules get at different locations in the cell and how they locate their partners is a major and partially unresolved question in biology that is paramount to signaling. Spatio-temporal correlations of fluctuating fluorescently tagged molecules reveal how they move, interact and bind in the different cellular compartments. Methods based on fluctuations represent a remarkable technical advancement in biological imaging. Here we discuss image analysis methods based on spatial and temporal correlation of fluctuations, Raster Image Correlation Spectroscopy (RICS), Number and & Brightness (N&B) and spatial cross-correlations that give us information about how individual molecules move in cells and interact with partners at the single molecule level. These methods can be implemented with a standard laser scanning microscope and produce a cellular level spatio-temporal map of molecular interactions.
Soft X-ray tomography (SXT) is an imaging technique capable of characterizing and quantifying the structural phenotype of cells. In particular, SXT is used to visualize the internal architecture of fully hydrated, intact eukaryotic and prokaryotic cells at high spatial resolution (50 nm or better). Image contrast in SXT is derived from the biochemical composition of the cell, and obtained without the need to use potentially damaging contrast-enhancing agents, such as heavy metals. The cells are simply cryopreserved prior to imaging, and are therefore imaged in a near-native state. As a complement to structural imaging by SXT, the same specimen can now be imaged by correlated cryo-light microscopy. By combining data from these two modalities specific molecules can be localized directly within the framework of a high-resolution, three-dimensional reconstruction of the cell. This combination of data types allows sophisticated analyses to be carried out on the impact of environmental and/or genetic factors on cell phenotypes.
cellular; correlated; cryo-light; morphology; multi-modal; three-dimensional
Significant progress in the molecular investigation of endogenous bioelectric signals during pattern formation in growing tissues have been enabled by recently-developed techniques. Ion flows and transmembrane gradients produced by ion channels and pumps are key regulators of cell proliferation, migration, and differentiation. Now, instructive roles for bioelectrical gradients in embryogenesis, regeneration, and neoplasm are being revealed through the use of fluorescent voltage reporters and functional experiments using well-characterized channel mutants. Transmembrane voltage gradients (Vmem) determine anatomical polarity and function as master regulators during appendage regeneration and embryonic left-right patterning. A state-of-the-art recent study reveals that they can also serve as prepatterns for gene expression domains during craniofacial patterning. Continued development of novel tools and better ways to think about physical controls of cell:cell interactions will lead to mastery of the morphogenetic information stored in physiological networks. This will enable fundamental advances in basic understanding of growth and form, as well as transformative biomedical applications in regenerative medicine.
bioelectricity; ion channels; membrane voltage; prepattern
This review, in the form of a FAQ, addresses outstanding questions about “shadow enhancers”, quasi-redundant cis-regulatory elements, and their proposed roles in transcriptional control. Questions include: What exactly are shadow enhancers? How many genes have shadow/redundant/distributed enhancers? How redundant are these elements? What is the function of distributed enhancers? How modular are enhancers? Is it useful to study a single enhancer in isolation? In addition, a revised definition of “shadow enhancers” is proposed, and possible mechanisms of shadow enhancer function and evolution are discussed.
cis-regulatory elements; enhancers; evolution; genomics; transcriptional regulation
Why do humans menstruate while most mammals do not? Here, we present our answer to this long-debated question, arguing that (i) menstruation occurs as a mechanistic consequence of hormone-induced differentiation of the endometrium (referred to as spontaneous decidualization, or SD); (ii) SD evolved because of maternal-fetal conflict; and (iii) SD evolved by genetic assimilation of the decidualization reaction, which is induced by the fetus in non-menstruating species. The idea that menstruation occurs as a consequence of SD has been proposed in the past, but here we present a novel hypothesis on how SD evolved. We argue that decidualization became genetically stabilized in menstruating lineages, allowing females to prepare for pregnancy without any signal from the fetus. We present three models for the evolution of SD by genetic assimilation, based on recent advances in our understanding of the mechanisms of endometrial differentiation and implantation. Testing these models will ultimately shed light on the evolutionary significance of menstruation, as well as on the etiology of human reproductive disorders like endometriosis and recurrent pregnancy loss.
genetic assimilation; maternal-fetal conflict; menstruation; molecular evolution
In sensory biology, a major outstanding question is how sensory receptor cells minimize noise while maximizing signal to set the detection threshold. This optimization could be problematic because the origin of both the signals and the limiting noise in most sensory systems is believed to lie in stimulus transduction. Signal processing in receptor cells can improve the signal-to-noise ratio. However, neural circuits can further optimize detection threshold by pooling signals from sensory receptor cells and processing them using a combination of linear and nonlinear filtering mechanisms. In the visual system, the noise limiting light detection has been assumed to arise from stimulus transduction in rod photoreceptors. In this context the evolutionary optimization of the signal-to-noise ratio in the retina has proven critical in allowing visual sensitivity to approach the limits set by the quantal nature of light. Here we discuss how noise in the mammalian retina is mitigated to allow for highly sensitive night vision.
linear filtering; nonlinear threshold; retinal circuitry; signal-to-noise ratio; signal transfer
Toxoplasma gondii is a highly successful parasite capable of infecting virtually all warm-blooded animals by actively invading nucleated host cells and forming a modified compartment where it replicates within the cytosol. The parasite-containing vacuole provides a safe haven even in professional phagocytes such as macrophages, which normally destroy foreign microbes. In effort to eliminate the parasite, the host up-regulates a family of immunity-related p47 GTPases (IRGs), which are recruited to the parasite-containing vacuole, resulting in membrane rupture and digestion of the parasite. To avoid this fate, highly virulent strains of Toxoplasma coat the external surface of their vacuole with a secretory serine/threonine kinase, known as ROP18. At this host-pathogen interface, ROP18 phosphorylates and inactivates IRGs, thereby protecting the parasite from killing. These findings reveal a novel molecular mechanism by which the parasite disarms host innate immunity
The generation of asymmetric cell shapes is a recurring theme in biology. In budding yeast, one form of cell asymmetry occurs for division and is generated by anisotropic growth of the mother cell to form a daughter cell bud. Previous genetic studies uncovered key roles for the small GTPase Cdc42 in organizing the actin cytoskeleton and vesicle delivery to the site of bud growth,(1,2) but a recent paper has also raised questions about how control of Cdc42 activity is integrated into a proposed hierarchical regulatory pathway that specifies a unique site of bud formation.(3)