Beverly A. Purnell

Fast and Slow

During gene transcription, some activator proteins bind cyclically to their promoters, with periodicities of ~30 seconds (fast cycling) or ~30 minutes (slow cycling). Karpova et al. now show that these different cycles are distinct but that the same transcription activator can engage in both cycling activities on the same promoter at the same time. It seems that the fast cycle is involved in transcription initiation, whereas the slow cycle modulates the number of promoters accessible for initiation. T. S. Karpova, M. J. Kim, C. Spriet, K. Nalley, T. J. Stasevich, Z. Kherrouche, L. Heliot, J. G. McNally, Concurrent fast and slow cycling of a transcriptional activator at an endogenous promoter. Science 319, 466-469 (2008). [Abstract] [Full Text]

Notch role in multipotency or cell fate

Notch signaling between stem cells and their daughters underlies their ability to produce many different cell types. Multipotent Drosophila intestinal stem cells (ISCs) generate either nutrient-absorbing enterocytes (ECs) or secretory enteroendocrine cells (EECs). Guo and Ohlstein investigated the role of Notch signaling in this process. They tracked ISC asymmetric divisions and found that EEC daughter cells, which have a low amount of Notch, signal back to the ISC in order to keep it multipotent. However, during EC production, ISCs activate strong Notch signaling in daughters. Thus, Notch signaling functions in two directions to achieve stem cell multipotency. Z. Guo, B. Ohlstein, Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science 350, aab0988 (2015). [Abstract] [Full Text]

Mouse work may lead to male contraceptive

Inhibiting the function of a protein involved in sperm maturation may help in the development of future male contraceptives. Unintended pregnancies are a major health issue worldwide. Although oral contraceptives were developed decades ago for use in women, there are no male oral contraceptives. Miyata et al. show that genetic deletion or drug inhibition of sperm-specific calcineurin enzymes in mice cause male sterility (see the Perspective by Castaneda and Matzuk). Although calcineurin inhibitors resulted in male infertility within 2 weeks, fertility recovered 1 week after halting drug administration. Because the sperm-specific calcineuin complex is also found in humans, its inhibition may be a strategy for developing reversible male contraceptives. H. Miyata, Y. Satouh, D. Mashiko, M. Muto, K. Nozawa, K. Shiba, Y. Fujihara, A. Isotani, K. Inaba, M. Ikawa, Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive. Science 350, 442–445 (2015). [Abstract] [Full Text] J. Castaneda, M. M. Matzuk, Toward a rapid and reversible male pill. Science 350, 385–386 (2015). [Abstract] [Full Text]

Brain keeps body size and shape in check

Drosophila Lgr3 defines a neural circuit for homeostatic regulation of body size. Animal systems show amazing left-right symmetry—think of how our legs or arms, or the legs or wings of an insect, are matched in size and shape. Environmental insults and growth defects can challenge these developmental programs. In order to limit the resultant variation, juvenile organisms buffer variability through homeostatic mechanisms, so that the correct final size is attained. Vallejo et al. report that the Drosophila brain mediates such homeostatic control through an insulin-like peptide Dilp8 that binds to the relaxin hormone receptor Lgr3. Lgr3-positive neurons distribute this information to other neuronal populations to adjust the hormones ecdysone, insulin, and juvenile hormone in a manner that stabilizes body and organ size. D. M. Vallejo, S. Juarez-Carreño, J. Bolivar, J. Morante, M. Dominguez, A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3. Science 350, aac6767 (2015). [Abstract] [Full Text]

Origin of Fish Pigment Cell for Pattern

Zebrafish adult pigment cells arise from several lineages and require thyroid hormone for pattern development. Zebrafish stripes arise from the interactions of pigment cells: black melanophores, iridescent iridophores, and yellow-orange xanthophores. Melanophores and iridophores develop from nerve-associated stem cells, but the origin of xanthophores is unclear. Two studies now reveal that adult xanthophores originate from xanthophores in embryonic and larval fish, when they proliferate to cover the skin before the arrival of black and silver cells in a striped arrangement. Mahalwar et al. show that xanthophores change their final shape and color depending on their location. In black cells, xanthophores appear faint and stellate, but in silver cells, they are bright and compact. Precise superposition creates the blue and golden colors. McMenamin et al. observe the loss of pigment in embryonic xanthophores and the later reappearance in the adult. They show that redifferentiation depends on the thyroid hormone that also limits melanophore population expansion. S. K. McMenamin, E. J. Bain, A. E. McCann, L. B. Patterson, D. S. Eom, Z. P. Waller, J. C. Hamill, J. A. Kuhlman, J. S. Eisen, D. M. Parichy, Thyroid hormone–dependent adult pigment cell lineage and pattern in zebrafish. Science 345, 1358–1361 (2014). [Abstract] [Full Text]

Human Stem Cell Expansion

The self-renewal of human hematopoietic stem cells in vitro is enhanced by the pyrimidoindole derivative UM171. Transfused blood saves lives. Despite the widespread use of this critical resource, it is difficult to increase blood cell numbers outside of the body. By screening thousands of small compounds, Fares et al. identified a molecule that expands human stem cell numbers in cord blood. The researchers generated many variations of that molecule and showed that one such compound provides even greater human blood cell expansion. If researchers can provide increased numbers of stem cells and progenitor cells, cord blood should find even greater use in the clinic. I. Fares, J. Chagraoui, Y. Gareau, S. Gingras, R. Ruel, N. Mayotte, E. Csaszar, D. J. H. F. Knapp, P. Miller, M. Ngom, S. Imren, D.-C. Roy, K. L. Watts, H.-P. Kiem, R. Herrington, N. N. Iscove, R. K. Humphries, C. J. Eaves, S. Cohen, A. Marinier, P. W. Zandstra, G. Sauvageau, Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345, 1509–1512 (2014). [Abstract] [Full Text]

Epigenetics Direct Transdifferentiation

Stepwise modifications to histones ensure efficient and reliable cell conversions in Caenorhabditis elegans. To make an entire animal, many and varied cell types form and interact. Some of these differentiated cells take a U-turn and can dedifferentiate or transdifferentiate to another cell fate. Although relatively rare in nature, Zuryn et al. followed such a program in the tiny roundworm Caenorhabditis elegans, where a rectal cell–to–motor neuron conversion is seen. Transcription factors with conserved roles in cell plasticity and terminal fate selection partner up with specific histone-modifying enzymes in discrete steps to specify separate sequential phases of cell identity. S. Zuryn, A. Ahier, M. Portoso, E. R. White, M.-C. Morin, R. Margueron, S. Jarriault, Sequential histone-modifying activities determine the robustness of transdifferentiation. Science 345, 826–829 (2014). [Abstract] [Full Text]

Establishing Memory of Gene Repression

Repression is perpetuated across generations and cell divisions via methylated histones and methylating enzymes. Although cells in the body contain the same DNA content, they can display widely varying form and function among tissues. This occurs through differential gene regulation and by the establishment of a type of memory of gene expression that is transmitted to daughter cells during cell division. Gaydos et al. report that, in nematodes, both sperm and oocytes transmitted a memory of chromatin repression to embryos in the form of modified histones. During DNA replication, modified histones were passed to daughter chromatids to provide chromatin memory for a few cell divisions. Histone-modifying enzymes replenished histone modifications and provided long-term chromatin memory. L. J. Gaydos, W. Wang, S. Strome, H3K27me and PRC2 transmit a memory of repression across generations and during development. Science 345, 1515–1518 (2014). [Abstract] [Full Text]

How Do Fingers Know Where to Grow

Modeling and experiments reveal how limb digits are patterned by three components. Most researchers today believe that each finger forms because of its unique position within the early limb bud. However, 30 years ago, developmental biologists proposed that the arrangement of fingers followed the Turing pattern, a self-organizing process during early embryo development. Raspopovic et al. provide evidence to support a Turing mechanism (see the Perspective by Zuniga and Zeller). They reveal that Bmp and Wnt signaling pathways, together with the gene Sox9, form a Turing network. The authors used this network to generate a computer model capable of accurately reproducing the patterns that cells follow as the embryo grows fingers. J. Raspopovic, L. Marcon, L. Russo, J. Sharpe, Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients. Science 345, 566–570 (2014). [Abstract][Full Text] A. Zuniga, R. Zeller, In Turing’s hands—the making of digits. Science 345, 516–517 (2014). [Abstract][Full Text]

Factor in Oocyte Assists Reprogramming

Human oocyte reprogramming of the somatic nucleus involves histone chaperone ASF1A. Unfertilized eggs contain components that can dedifferentiate other cells that have gone down the path toward a specific cell fate. Gonzalez-Muñoz et al. show that the protein-folding factor ASF1A facilitates this reprogramming event and acts at a particular phase of germ cell division termed metaphase II. ASF1A helps turn differentiated cells such as human adult dermal fibroblasts into undifferentiated pluripotent stem cells. E. Gonzalez-Muñoz, Y. Arboleda-Estudillo, H. H. Otu, J. B. Cibelli, Histone chaperone ASF1A is required for maintenance of pluripotency and cellular reprogramming. Science 345, 822–825 (2014). [Abstract] [Full Text]