Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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Combinatorial code governing cellular responses to complex stimuli Nature Communications 6, Article number: 6847 doi:10.1038/ncomms7847 Cells adapt to their environment through the integration of complex signals. Multiple signals can induce synergistic or antagonistic interactions, currently considered as homogenous behaviours. Here, we use a systematic theoretical approach to enumerate the possible interaction profiles for outputs measured in the conditions 0 (control), signals X, Y, X+Y. Combinatorial analysis reveals 82 possible interaction profiles, which we biologically and mathematically grouped into five positive and five negative interaction modes. To experimentally validate their use in living cells, we apply an original computational workflow to transcriptomics data of innate immune cells integrating physiopathological signal combinations. Up to 9 of the 10 defined modes coexisted in context-dependent proportions. Each interaction mode was preferentially used in specific biological pathways, suggesting a functional role in the adaptation to multiple signals. Our work defines an exhaustive map of interaction modes for cells integrating pairs of physiopathological and pharmacological stimuli. http://www.nature.com/ncomms/2015/150421/ncomms7847/full/ncomms7847.html
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...the biggest mystery of the cell cycle resolved? Journal of Physics: Condensed Matter doi:10.1088/0953-8984/21/50/502101 Spindle checkpoint regulated by nonequilibrium collective spindle-chromosome interaction; relationship to single DNA molecule force-extension formula The spindle checkpoint, which blocks segregation until all sister chromatid pairs have been stably connected to the two spindle poles, is perhaps the biggest mystery of the cell cycle. The main reason seems to be that the spatial correlations imposed by microtubules between stably attached kinetochores and the nonlinear dependence of the system on the increasing number of such kinetochores have been disregarded in earlier spindle checkpoint studies. From these missing parts a non-equilibrium collective spindle–chromosome interaction is obtained here for budding yeast (Saccharomyces cerevisiae) cells. The interaction, which is based on a non-equilibrium statistical mechanics, can sense and count the number of stably attached kinetochores and sense the threshold for segregation. It blocks segregation until all sister chromatids pairs have been bi-oriented and regulates tension such that segregation becomes synchronized, thus explaining how the cell might decide to segregate replicated chromosomes. The model also predicts kinetochore oscillations at a frequency which agrees well with observation. Finally, a relationship between this spindle–chromosome dynamics and the force-extension formula obtained in a single DNA molecule experiment is obtained. http://iopscience.iop.org/0953-8984/21/50/502101
Read the whole paper and see the detailed mathematical description of the physical model describing this complex machinery. Very simple... Really cool! :)Dionisio_{April 23, 2015
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Unsolved mysteries in NLR biology Christopher Lupfer and Thirumala-Devi Kanneganti Front. Immunol. doi: 10.3389/fimmu.2013.00285 NOD-like receptors (NLRs) are a class of cytoplasmic pattern-recognition receptors. Although most NLRs play some role in immunity, their functions range from regulating antigen presentation (NLRC5, CIITA) to pathogen/damage sensing (NLRP1, NLRP3, NLRC1/2, NLRC4) to suppression or modulation of inflammation (NLRC3, NLRP6, NLRP12, NLRX1). However, NLRP2, NLRP5, and NLRP7 are also involved in non-immune pathways such as embryonic development. In this review, we highlight some of the least well-understood aspects of NLRs, including the mechanisms by which they sense pathogens or damage. NLRP3 recognizes a diverse range of stimuli and numerous publications have presented potential unifying models for NLRP3 activation, but no single mechanism proposed thus far appears to account for all possible NLRP3 activators. Additionally, NLRC3, NLRP6, and NLRP12 inhibit NF-?B activation, but whether direct ligand sensing is a requirement for this function is not known. Herein, we review the various mechanisms of sensing and activation proposed for NLRP3 and other inflammasome activators. We also discuss the role of NLRC3, NLRP6, NLRP12, and NLRX1 as inhibitors and how they are activated and function in their roles to limit inflammation. Finally, we present an overview of the emerging roles that NLRP2, NLRP5, and NLRP7 play during embryonic development and postulate on the potential pathways involved. The role of NLRs in immune function is unequivocal. However, there is much molecular, biochemical and structural research which remains to be done to better understand how NLRs are activated and regulated. The fact that after a decade of research, new inflammasome activators are still being discovered may indicate that more NLRs fill this function than those previously described. Furthermore, recent studies have also validated roles for NLRP5 in embryonic development, although the exact mechanisms underlying these observations have not been elucidated (123–125). With more than 10 NLRs unstudied, it will be of interest to determine the function of these remaining NLRs in inflammation and development. http://journal.frontiersin.org/article/10.3389/fimmu.2013.00285/abstract
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Small Cells—Big Future Mol Biol Cell. doi: 10.1091/mbc.E10-05-0399 PMCID: PMC2982112 Bonnie L. Bassler Every living organism—including Earth's simplest life form, the bacterium—is loaded with molecular devices that are breathtaking in their design, complexity, and efficiency. Bacteria invented the rules for cellular organization. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982112/
say what? design? invented the rules?Dionisio_{April 20, 2015
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Nat Rev Mol Cell Biol. doi: 10.1038/nrm3775 PMCID: PMC4211427 NIHMSID: NIHMS604041 Organization and execution of the epithelial polarity programme Enrique Rodriguez-Boulan and Ian G. Macara Epithelial cells require apical–basal plasma membrane polarity to perform crucial vectorial transport functions and cytoplasmic polarity to generate different cell progenies for tissue morphogenesis. The establishment and maintenance of a polarized epithelial cell with apical, basolateral and ciliary surface domains is guided by an epithelial polarity programme (EPP) that is controlled by a network of protein and lipid regulators. The EPP is organized in response to extracellular cues and is executed through the establishment of an apical-basal axis, intercellular junctions, epithelial–specific cytoskeletal rearrangements and a polarized trafficking machinery. Recent studies have provided insight on the interactions of the EPP with the polarized trafficking machinery and how they regulate epithelial polarization and depolarization. The EPP integrates numerous processes and touches on almost every aspect of cell biology. Many of the mechanistic details of this integration remain to be identified. One complication is that the execution of the EPP may vary markedly in different locations or physiological contexts, often using the same components but in cell-type specific ways. For example, in Drosophila, Crb is only essential for apical specification during morphogenesis when adherens junctions are rapidly expanding or turning over 15. Moreover, basolateral polarity proteins such as Lgl are not essential for the maintenance of polarity in late-stage embryogenesis, but are required during gastrulation. As an example from mammalian cells, the initial landmark for the apical domain in single cells grown in 3D culture is the site of abscission during cytokinesis, but this is unlikely to be true during development, when single cells are probably not isolated from each other, and neighboring cells will provide spatial information through cadherin-based adhesion. An important future goal, therefore, will be to understand how the EPP operates in specific, biologically relevant contexts. It will also be central to gain better temporal and spatial resolution of the initial stages of epithelial polarization. We do not know which proteins first arrive at the presumptive membrane domains, or at the tight junctions that form between the apical and lateral domains. We also need to learn more about the interconnected signaling between sensors, such as the primary cilium, integrins and cadherins, and the EPP. Our knowledge of the links between the effectors of the EPP, particularly the vesicle trafficking machinery and the polarity proteins, is also still very superficial. A comprehensive understanding of these links will surely inform our knowledge of human disease, which so often involves epithelial cells. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211427/
Dionisio_{April 19, 2015
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Nat Rev Mol Cell Biol. doi: 10.1038/nrm3187 PMCID: PMC3282063 NIHMSID: NIHMS355294 Asifa Akhtar, Elaine Fuchs, Tim Mitchison, Reuben J. Shaw, Daniel St Johnston, Andreas Strasser, Susan Taylor, Claire Walczak, and Marino Zerial A.A. The dynamics and quantitative nature of how various pathways and macromolecular complexes function remain poorly understood. We are also beginning to appreciate that spatial and temporal control contribute important regulatory steps in gene regulation. The same molecule in different cellular compartments may have very different regulatory functions, which could be missed during biochemical analyses. If we can gear our research to go from qualitative to quantitative biology and understand the real dynamics of our favourite molecules in vivo, we will make a great leap in our understanding of various cellular pathways. E.F. The most pressing questions in my field are in many ways no different than they were 20–30 years ago, but the answers are closer at hand. How do stem cells build tissues during normal homeostasis and wound repair, and how does this go awry in human diseases, including cancers? And how can we exploit this information to understand the bases of these different diseases and develop new and improved therapies for the treatment of these disorders? With the recombinant DNA technology revolution of the early 1980s and the human genome revolution at the turn of the century, the interface between basic science and medicine is closing at a pace we never imagined possible as students. The tools and technologies available to address fundamental biological questions are advancing at a ferocious rate. The challenge ahead will be to ask the right questions and creatively develop strategies that exploit these tools to bridge this gap and revolutionize medicine. R.J.S. A big challenge going forward comes out of this explosion of data from different systems: bridging the omics studies (RNAi screens, ChIP–seq, phosphoproteomes and mass spectrometry interactomes) to define what the key rate-limiting proteins in any biological process are. The world still needs careful mechanistic dissection of individual proteins and functions, which sometimes gets lost amidst the push for larger and larger datasets. Taking the findings in cellular systems and then bridging that to the physiology and pathology of diseases in the intact higher organism also remains a key challenge. D. St J. Most recent cell biology has focused on a relatively small number of cell types (most often, unpolarized, transformed tissue culture cells) and has largely overlooked the astonishing array of different cell types with specialized functions that occur in vivo. I think that one of the key challenges for the future is to develop better ways of performing in vivo cell biology to examine cellular behaviours in the context of organs and tissues. The ability to induce iPS cells to form organs in culture will be an enormous help for this type of work. A.S. One challenge is elucidating the precise definition of how cellular differentiation and functional activation are controlled; that is, how the many transcriptional regulators, modifications to the genome (for example, through methylation) and posttranscriptional regulatory processes (for example, through the impact of miRNAs) interact to regulate stepwise changes towards a differentiated state. Another is defining the mechanisms that regulate non-apoptotic, but still genetically programmed, cell death pathways and the definition of their role in normal physiology (for example, during embryonic development and tissue homeostasis in adulthood). S.T. The biggest challenge for biology is always to ask the right question, and this is even more important now as technologies advance so rapidly. In our frenzy to collect more and more data, we need to learn how to ask the right questions and how to extract useful information from that data. In parallel with systems biology, we must have a mechanistic understanding of biology. Without understanding the underlying biochemical principles, the data mean little. Just as we need classical physiology to understand how molecules work in whole animals, we need biochemistry to have a true mechanistic understanding of biological events. C.E.W. While the genomic revolution has provided us with a wealth of potentially important molecules, the large-scale functional genomics screens only scratch the surface of understanding the mechanisms by which these proteins act. The challenge is to develop creative approaches to answer the most fundamental biological questions. For example, although proteomic approaches have identified all of the components of the mitotic spindle and genome-wide screens have identified an array of molecules that affect the mitotic spindle, we still do not understand the fundamental mechanism by which each chromosome moves to the spindle equator and then is partitioned to the daughter cells. M.Z. Cell biology must move to tissues and organisms. An outstanding problem is bridging between scales. Understanding how cellular components form complexes, how these assemble into organelles and how organelles form cells, which build organs and organisms, poses enormous technical and conceptual challenges. The integration of biological processes is one of the most difficult problems we face. Solving these problems requires trespassing across the traditional borders between fields and developing new experimental and analytical methods. At present, we can explain only small parts of biological mechanisms: we see a few pieces of a puzzle, but for the whole picture we must draw in complexity. There are no current solutions at the modelling or computational level. This problem requires the development of new theories. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282063/
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Cell Biology: The Endless Frontier Bruce Alberts University of California, San Francisco, San Francisco, CA 94143 Cell biology has come a very long way since my early days as a scientist. It seems very safe to predict that the more we learn about cells and organisms, the more intriguing will be the new mysteries that remain to be solved. Our view of the cell today is certain to seem incredibly simplistic to anyone rereading these brief essays on the 100th anniversary of ASCB, in 2060. To me, there is nothing more grand about science than this, its “endless frontier.” http://www.molbiolcell.org/content/21/22/3785
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How Far Will We See in the Future? Kim Nasmyth University of Oxford, Department of Biochemistry, Oxford OX1 3QU, United Kingdom Crucially, because previous discoveries have revealed more ignorance than understanding, we are paradoxically more ignorant than we have ever been. http://www.molbiolcell.org/content/21/22/3813
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Remaining Mysteries of the Cytoplasm Timothy J. Mitchison Department of Systems Biology, Systems Biology, Harvard Medical School, Boston, MA 02115 Nothing epitomizes the mystery of life more than the spatial organization and dynamics of the cytoplasm. How can a bunch of molecules, no matter how sophisticated, generate spatially complex behavior on a scale that is much larger than the molecules themselves? http://www.molbiolcell.org/content/21/22/3811Dionisio_{April 19, 2015
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Embryo engineering alarm: A prudent path forward for genomic engineering and germline gene modification http://www.sciencemag.org/content/347/6228/1301.summaryDionisio_{March 21, 2015
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The time allotted for the current learning phase is about to end. Next moving on to another phase in the project. Will try to stop by and keep an eye on what's going on here -specially the interesting discussions.Dionisio_{February 20, 2015
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Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins. doi: 10.1007/978-94-007-7893-1_3. Collagens are the most abundant components of the extracellular matrix and many types of soft tissues. Elastin is another major component of certain soft tissues, such as arterial walls and ligaments. Many other molecules, though lower in quantity, function as essential components of the extracellular matrix in soft tissues. http://www.ncbi.nlm.nih.gov/pubmed/24443019 http://link.springer.com/chapter/10.1007/978-94-007-7893-1_3
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NIH-Supported Researchers Map Epigenome of More than 100 Tissue, Cell Types “This represents a major advance in the ongoing effort to understand how the 3 billion letters of an individual’s DNA instruction book are able to instruct vastly different molecular activities, depending on the cellular context,” said NIH Director Francis Collins, M.D., Ph.D. “This outpouring of data-rich publications, produced by a remarkable team of creative scientists, provides powerful momentum for the rapidly growing field of epigenomics.” “What the Roadmap Epigenomics Program has delivered is a way to look at the human genome in its living, breathing nature from cell type to cell type,” said Manolis Kellis, Ph.D., professor of computer science at the Massachusetts Institute of Technology, Cambridge, and senior author of the paper. “Today, sequencing the human genome can be done rapidly and cheaply, but interpreting the genome remains a challenge,” said Bing Ren, Ph.D., professor of cellular and molecular medicine at the University of California, San Diego, and co-author of the Nature paper and several of the associated papers. “These 111 reference epigenome maps are essentially a vocabulary book that helps us decipher each DNA segment in distinct cell and tissue types. These maps are like snapshots of the human genome in action.” “This is the most comprehensive catalog of epigenomic data from primary human cells and tissues to date,” said Lisa Helbling Chadwick, Ph.D., project team leader and a program director at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. “This coordinated effort, along with uniform data processing, makes it much easier for researchers to make direct comparisons across the entire data set.” “Researchers from the 88 projects supported by the program, including those from this recent series of papers, have propelled the development of new epigenomic technologies,” said John Satterlee, Ph.D., co-coordinator of the Roadmap Epigenomics Program, and program director at the National Institute on Drug Abuse (NIDA), part of NIH. Satterlee added that the work of this program has served as a foundation for continued exploration of the human epigenome through the International Human Epigenome Consortium External Web Site Policy. “With this increased understanding of the full epigenome, and the datasets available to the entire scientific community, the NIH Common Fund is striving to catalyze future research, to aid the understanding of how epigenomics plays a role in human diseases, with the expectation that further studies will identify early indications of disease and targets for therapeutics,” said James Anderson, M.D., Ph.D., director of NIH Division of Program Coordination, Planning, and Strategic Initiatives that oversees the NIH Common Fund. http://www.biosciencetechnology.com/news/2015/02/nih-supported-researchers-map-epigenome-more-100-tissue-cell-types?et_cid=4421938&et_rid=653535995&location=top
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Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq DOI: 10.1126/science.aaa1934 Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity. http://www.sciencemag.org/content/early/2015/02/18/science.aaa1934
complex, layered regulatory code? Hmmm... where did that come from? FUCA, LUCA? how?Dionisio_{February 20, 2015
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Pervasive and Essential Roles of the Top3-Rmi1 Decatenase Orchestrate Recombination and Facilitate Chromosome Segregation in Meiosis DOI: http://dx.doi.org/10.1016/j.molcel.2015.01.021 The Bloom’s helicase ortholog, Sgs1, plays central roles to coordinate the formation and resolution of joint molecule intermediates (JMs) during meiotic recombination in budding yeast. Sgs1 can associate with type-I topoisomerase Top3 and its accessory factor Rmi1 to form a conserved complex best known for its unique ability to decatenate double-Holliday junctions. Contrary to expectations, we show that the strand-passage activity of Top3-Rmi1 is required for all known functions of Sgs1 in meiotic recombination, including channeling JMs into physiological crossover and noncrossover pathways, and suppression of non-allelic recombination. We infer that Sgs1 always functions in the context of the Sgs1-Top3-Rmi1 complex to regulate meiotic recombination. In addition, we reveal a distinct late role for Top3-Rmi1 in resolving recombination-dependent chromosome entanglements to allow segregation at anaphase. Surprisingly, Sgs1 does not share this essential role of Top3-Rmi1. These data reveal an essential and pervasive role for the Top3-Rmi1 decatenase during meiosis. http://www.cell.com/molecular-cell/abstract/S1097-2765(15)00022-2
Did they say 'orchestrate'? :) Contrary to expectations,? what expectations? Surprisingly, ? why? did they expect something else?Dionisio_{February 20, 2015
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Human Promoters Are Intrinsically Directional DOI: http://dx.doi.org/10.1016/j.molcel.2014.12.029 Divergent transcription, in which reverse-oriented transcripts occur upstream of eukaryotic promoters in regions devoid of annotated genes, has been suggested to be a general property of active promoters. Here we show that the human basal RNA polymerase II transcriptional machinery and core promoter are inherently unidirectional and that reverse-oriented transcripts originate from their own cognate reverse-directed core promoters. In vitro transcription analysis and mapping of nascent transcripts in HeLa cells revealed that sequences at reverse start sites are similar to those of their forward counterparts. The use of DNase I accessibility to define proximal promoter borders revealed that about half of promoters are unidirectional and that unidirectional promoters are depleted at their upstream edges of reverse core promoter sequences and their associated chromatin features. Divergent transcription is thus not an inherent property of the transcription process but rather the consequence of the presence of both forward- and reverse-directed core promoters. http://www.cell.com/molecular-cell/abstract/S1097-2765(14)01007-7?elsca1=etoc&elsca2=email&elsca3=1097-2765_20150219_57_4_&elsca4=Cell%20Press
Dionisio_{February 20, 2015
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Ectosomes and exosomes: shedding the confusion between extracellular vesicles DOI: http://dx.doi.org/10.1016/j.tcb.2015.01.004 Long- and short-distance communication can take multiple forms. Among them are exosomes and ectosomes, extracellular vesicles (EVs) released from the cell to deliver signals to target cells. While most of our understanding of how these vesicles are assembled and work comes from mechanistic studies performed on exosomes, recent studies have begun to shift their focus to ectosomes. Unlike exosomes, which are released on the exocytosis of multivesicular bodies (MVBs), ectosomes are ubiquitous vesicles assembled at and released from the plasma membrane. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(15)00015-X
Several 'how?' and' why?' questions come to mind, don't they? :)Dionisio_{February 20, 2015
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Engineering the extracellular matrix for clinical applications: endoderm, mesoderm, and ectoderm. doi: 10.1002/biot.201300120 Tissue engineering is rapidly progressing from a research-based discipline to clinical applications. Emerging technologies could be utilized to develop therapeutics for a wide range of diseases, but many are contingent on a cell scaffold that can produce proper tissue ultrastructure. The extracellular matrix, which a cell scaffold simulates, is not merely a foundation for tissue growth but a dynamic participant in cellular crosstalk and organ homeostasis. Cells change their growth rates, recruitment, and differentiation in response to the composition, modulus, and patterning of the substrate on which they reside. Cell scaffolds can regulate these factors through precision design, functionalization, and application. The ideal therapy would utilize highly specialized cell scaffolds to best mimic the tissue of interest. This paper discusses advantages and challenges of optimized cell scaffold design in the endoderm, mesoderm, and ectoderm for clinical applications in tracheal transplant, cardiac regeneration, and skin grafts, respectively. http://www.ncbi.nlm.nih.gov/pubmed/24390851
Do they have to 'design' something in order to imitate the functioning of biological components that allegedly were not designed? :)Dionisio_{February 19, 2015
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Chromatin and Transcriptional Tango on the Immune Dance Floor doi: 10.3389/fimmu.2014.00631 http://journal.frontiersin.org/article/10.3389/fimmu.2014.00631/full The process of generating differentiated cell types performing specific effector functions from their respective undifferentiated precursors is dictated by extracellular signals, which alter the host cell’s capacity to perform cellular functions. One major mechanism for bringing about such changes is at the level of transcription. Thus, the transcription-related induction of previously silent genes and suppression of active genes in response to extracellular signals can result in the acquisition of new functions by the cells. The general transcriptional machinery, which comprised of RNA Polymerase II and associated initiation factors, assemble into preinitiation complexes at the core promoters of eukaryotic protein coding genes in response to the signal-dependent activation of corresponding regulatory factors that bind to promoter and enhancer elements (1). The rate of formation and/or stability of these complexes, which can be modulated both by enhancer–promoter interactions and by chromatin structural modifications, dictate the transcriptional regulation of the corresponding gene. Such coordinated temporal and spatial regulation of gene expression in response to specific signals determines lineage differentiation, cellular proliferation, and development (2).
It takes two to tango, but apparently there are more dancers in the center of the ballroom. :)Dionisio_{February 19, 2015
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AIDing chromatin and transcription-coupled orchestration of immunoglobulin class-switch recombination 10.3389/fimmu.2014.00120 Secondary diversification of the antibody repertoire upon antigenic challenge, in the form of immunoglobulin heavy chain (IgH) class-switch recombination (CSR) endows mature, naïve B cells in peripheral lymphoid organs with a limitless ability to mount an optimal humoral immune response, thus expediting pathogen elimination. CSR replaces the default constant (CH) region exons (C?) of IgH with any of the downstream CH exons (C?, C?, or C?), thereby altering effector functions of the antibody molecule. This process depends on, and is orchestrated by, activation-induced deaminase (AID), a DNA cytidine deaminase that acts on single-stranded DNA exposed during transcription of switch (S) region sequences at the IgH locus. DNA lesions thus generated are processed by components of several general DNA repair pathways to drive CSR. Given that AID can instigate DNA lesions and genomic instability, stringent checks are imposed that constrain and restrict its mutagenic potential. In this review, we will discuss how AID expression and substrate specificity and activity is rigorously enforced at the transcriptional, post-transcriptional, post-translational, and epigenetic levels, and how the DNA-damage response is choreographed with precision to permit targeted activity while limiting bystander catastrophe. http://journal.frontiersin.org/article/10.3389/fimmu.2014.00120/abstract
Did they write 'orchestrated' and 'choreographed' ? :)Dionisio_{February 19, 2015
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Regulation of Immunoglobulin Class-Switch Recombination: Choreography of Noncoding Transcription, Targeted DNA Deamination, and Long-Range DNA Repair doi:10.1016/B978-0-12-800267-4.00001-8 Upon encountering antigens, mature IgM-positive B lymphocytes undergo class-switch recombination (CSR) wherein exons encoding the default C? constant coding gene segment of the immunoglobulin (Ig) heavy-chain (Igh) locus are excised and replaced with a new constant gene segment (referred to as “Ch genes”, e.g., C?, C?, or C?). The B cell thereby changes from expressing IgM to one producing IgG, IgE, or IgA, with each antibody isotype having a different effector function during an immune reaction. CSR is a DNA deletional-recombination reaction that proceeds through the generation of DNA double-strand breaks (DSBs) in repetitive switch (S) sequences preceding each Ch gene and is completed by end-joining between donor S? and acceptor S regions. CSR is a multistep reaction requiring transcription through S regions, the DNA cytidine deaminase AID, and the participation of several general DNA repair pathways including base excision repair, mismatch repair, and classical nonhomologous end-joining. In this review, we discuss our current understanding of how transcription through S regions generates substrates for AID-mediated deamination and how AID participates not only in the initiation of CSR but also in the conversion of deaminated residues into DSBs. Additionally, we review the multiple processes that regulate AID expression and facilitate its recruitment specifically to the Ig loci, and how deregulation of AID specificity leads to oncogenic translocations. Finally, we summarize recent data on the potential role of AID in the maintenance of the pluripotent stem cell state during epigenetic reprogramming. http://www.sciencedirect.com/science/article/pii/B9780128002674000018 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150736/
Did they say 'choreography'? :) Pretty simple, isn't it? Sometimes I highlight text that I might have further questions on, but this time I would have to highlight almost the entire article.Dionisio_{February 19, 2015
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Epigenetic function of activation-induced cytidine deaminase and its link to lymphomagenesis. doi: 10.3389/fimmu.2014.00642 Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination of immunoglobulin (Ig) genes during B cell maturation and immune response. Expression of AID is tightly regulated due to its mutagenic and recombinogenic potential, which is known to target not only Ig genes, but also non-Ig genes, contributing to lymphomagenesis. In recent years, a new epigenetic function of AID and its link to DNA demethylation came to light in several developmental systems. In this review, we summarize existing evidence linking deamination of unmodified and modified cytidine by AID to base-excision repair and mismatch repair machinery resulting in passive or active removal of DNA methylation mark, with the focus on B cell biology. We also discuss potential contribution of AID-dependent DNA hypomethylation to lymphomagenesis. http://journal.frontiersin.org/article/10.3389/fimmu.2014.00642/abstract http://www.ncbi.nlm.nih.gov/pubmed/25566255
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B cell TLR1/2, TLR4, TLR7 and TLR9 interact in induction of class switch DNA recombination: modulation by BCR and CD40, and relevance to T-independent antibody responses. doi: 10.3109/08916934.2014.993027. http://www.ncbi.nlm.nih.gov/pubmed/25536171Dionisio_{February 19, 2015
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Pathogen manipulation of B cells: the best defence is a good offence DOI: 10.1038/nrmicro3415 B cells have long been regarded as simple antibody production units, but are now becoming known as key players in both adaptive and innate immune responses. However, several bacteria, viruses and parasites have evolved the ability to manipulate B cell functions to modulate immune responses. Pathogens can affect B cells indirectly, by attacking innate immune cells and altering the cytokine environment, and can also target B cells directly, impairing B cell-mediated immune responses. In this Review, we provide a summary of recent advances in elucidating direct B cell-pathogen interactions and highlight how targeting this specific cell population benefits different pathogens. http://www.nature.com/nrmicro/journal/v13/n3/full/nrmicro3415.html http://www.researchgate.net/publication/272100693_Pathogen_manipulation_of_B_cells_the_best_defence_is_a_good_offence
Dionisio_{February 19, 2015
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Application of metabolomics in autoimmune diseases: Insight into biomarkers and pathology DOI: 10.1016/j.jneuroim.2015.01.001 Metabolomics has recently become a new technology using mass spectrometry (MS) and high-resolution proton nuclear magnetic resonance (NMR) to access metabolite profiles in biofluids or tissue extracts for the detection of biomarker molecules and biochemical effects induced by a disease or its therapeutic intervention. This review outlines recent advances in the use of metabolomic techniques to study autoimmune diseases (ADs), including multiple sclerosis (MS), rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), autoimmune diabetes et al. Many studies have demonstrated that AD patients including subtypes of some diseases, and healthy individuals can be distinguished using metabolic profiling accompanied with well-established data analysis tools including principal component analysis (PCA) and partial least squares (PLS). These metabolites not only affect glucose, amino acid and lipid metabolism, but also involve alteration of neurotransmitters, nucleotides, immune responses and anti-inflammatory responses. Knowledge of unique metabolomic fingerprint in ADs could be useful for diagnosis, treatment, and detection mechanisms of diseases. http://www.jni-journal.com/article/S0165-5728(15)00003-X/abstract http://www.ncbi.nlm.nih.gov/pubmed/25669996 http://www.researchgate.net/publication/271225856_Application_of_metabolomics_in_autoimmune_diseases_Insight_into_biomarkers_and_pathology
So many things can mess up the delicate biological systems. How can they function at all?Dionisio_{February 19, 2015
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B10 Cells: A Functionally Defined Regulatory B Cell Subset. DOI: 10.4049/jimmunol.1401329 B cells are commonly thought to enhance inflammatory immune responses. However, specific regulatory B cell subsets recently were identified that downregulate adaptive and innate immunity, inflammation, and autoimmunity through diverse molecular mechanisms. In both mice and humans, a rare, but specific, subset of regulatory B cells is functionally characterized by its capacity to produce IL-10, a potent inhibitory cytokine. For clarity, this regulatory B cell subset has been labeled as B10 cells, because their ability to downregulate immune responses and inflammatory disease is fully attributable to IL-10, and their absence or loss exacerbates disease symptoms in mouse models. This review preferentially focuses on what is known about mouse B10 cell development, phenotype, and effector function, as well as on mechanistic studies that demonstrated their functional importance during inflammation, autoimmune disease, and immune responses. Copyright © 2015 by The American Association of Immunologists, Inc. http://www.researchgate.net/publication/272097721_B10_Cells_A_Functionally_Defined_Regulatory_B_Cell_Subset http://www.jimmunol.org/content/194/4/1395.short
http://www.jimmunol.org/content/194/4/1395.shortDionisio_{February 19, 2015
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The extracellular matrix: Structure, composition, age-related differences, tools for analysis and applications for tissue engineering. doi: 10.1177/2041731414557112 The extracellular matrix is a structural support network made up of diverse proteins, sugars and other components. It influences a wide number of cellular processes including migration, wound healing and differentiation, all of which is of particular interest to researchers in the field of tissue engineering. Understanding the composition and structure of the extracellular matrix will aid in exploring the ways the extracellular matrix can be utilised in tissue engineering applications especially as a scaffold. This review summarises the current knowledge of the composition, structure and functions of the extracellular matrix and introduces the effect of ageing on extracellular matrix remodelling and its contribution to cellular functions. Additionally, the current analytical technologies to study the extracellular matrix and extracellular matrix-related cellular processes are also reviewed. http://www.ncbi.nlm.nih.gov/pubmed/25610589
Dionisio_{February 18, 2015
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Deciphering the genetic programme triggering timely and spatially-regulated chitin deposition doi: 10.1371/journal.pgen.1004939 Organ and tissue formation requires a finely tuned temporal and spatial regulation of differentiation programmes. This is necessary to balance sufficient plasticity to undergo morphogenesis with the acquisition of the mature traits needed for physiological activity. Here we addressed this issue by analysing the deposition of the chitinous extracellular matrix of Drosophila, an essential element of the cuticle (skin) and respiratory system (tracheae) in this insect. Chitin deposition requires the activity of the chitin synthase Krotzkopf verkehrt (Kkv). Our data demonstrate that this process equally requires the activity of two other genes, namely expansion (exp) and rebuf (reb). We found that Exp and Reb have interchangeable functions, and in their absence no chitin is produced, in spite of the presence of Kkv. Conversely, when Kkv and Exp/Reb are co-expressed in the ectoderm, they promote chitin deposition, even in tissues normally devoid of this polysaccharide. Therefore, our results indicate that both functions are not only required but also sufficient to trigger chitin accumulation. We show that this mechanism is highly regulated in time and space, ensuring chitin accumulation in the correct tissues and developmental stages. Accordingly, we observed that unregulated chitin deposition disturbs morphogenesis, thus highlighting the need for tight regulation of this process. In summary, here we identify the genetic programme that triggers the timely and spatially regulated deposition of chitin and thus provide new insights into the extracellular matrix maturation required for physiological activity. http://www.ncbi.nlm.nih.gov/pubmed/25617778 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004939
Dionisio_{February 18, 2015
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Maternal-zygotic knockout reveals a critical role of Cdx2 in the morula to blastocyst transition doi:10.1016/j.ydbio.2014.12.004 The first lineage segregation in the mouse embryo generates the inner cell mass (ICM), which gives rise to the pluripotent epiblast and therefore the future embryo, and the trophectoderm (TE), which will build the placenta. The TE lineage depends on the transcription factor Cdx2. However, when Cdx2 first starts to act remains unclear. Embryos with zygotic deletion of Cdx2 develop normally until the late blastocyst stage leading to the conclusion that Cdx2 is important for the maintenance but not specification of the TE. In contrast, down-regulation of Cdx2 transcripts from the early embryo stage results in defects in TE specification before the blastocyst stage. Here, to unambiguously address at which developmental stage Cdx2 becomes first required, we genetically deleted Cdx2 from the oocyte stage using a Zp3-Cre/loxP strategy. Careful assessment of a large cohort of Cdx2 maternal-zygotic null embryos, all individually filmed, examined and genotyped, reveals an earlier lethal phenotype than observed in Cdx2 zygotic null embryos that develop until the late blastocyst stage. The developmental failure of Cdx2 maternal-zygotic null embryos is associated with cell death and failure of TE specification, starting at the morula stage. These results indicate that Cdx2 is important for the correct specification of TE from the morula stage onwards and that both maternal and zygotic pools of Cdx2 are required for correct pre-implantation embryogenesis. http://www.sciencedirect.com/science/article/pii/S0012160614006307
Dionisio_{February 18, 2015
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Epigenomic footprints across 111 reference epigenomes reveal tissue-specific epigenetic regulation of lincRNAs doi:10.1038/ncomms7370 Tissue-specific expression of lincRNAs suggests developmental and cell-type-specific functions, yet tissue specificity was established for only a small fraction of lincRNAs. Here, by analysing 111 reference epigenomes from the NIH Roadmap Epigenomics project, we determine tissue-specific epigenetic regulation for 3,753 (69% examined) lincRNAs, with 54% active in one of the 14 cell/tissue clusters and an additional 15% in two or three clusters. A larger fraction of lincRNA TSSs is marked in a tissue-specific manner by H3K4me1 than by H3K4me3. The tissue-specific lincRNAs are strongly linked to tissue-specific pathways and undergo distinct chromatin state transitions during cellular differentiation. Polycomb-regulated lincRNAs reside in the bivalent state in embryonic stem cells and many of them undergo H3K27me3-mediated silencing at early stages of differentiation. The exquisitely tissue-specific epigenetic regulation of lincRNAs and the assignment of a majority of them to specific tissue types will inform future studies of this newly discovered class of genes. http://www.nature.com/ncomms/2015/150218/ncomms7370/full/ncomms7370.html
Dionisio_{February 18, 2015
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