Let it RE:IN: integrating experimental observations to predict pluripotency network behaviour
Our ability to reprogram cells and induce transitions between states has fast become a commonplace tool, but our understanding of the underlying processes and capacity to predict these is still relatively rudimentary. A new article by Dunn et al (2019) combines a computational reasoning approach with experimental observation to construct a network-level understanding of the transcription factors instructing acquisition of naïve pluripotency during reprogramming. (Source: EMBO Journal)
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Rackham, O. J., Polo, J. M. Tags: Stem Cells, Systems & Computational Biology, Transcription News [amp ] Views Source Type: research
Alpha-ketoglutarate: a "magic" metabolite in early germ cell development
A causal relationship between cell metabolism and the fate of pluripotent stem cells through epigenome regulation is emerging. A recent study shows that the tricarboxylic acid cycle intermediate alpha-ketoglutarate (αKG) can both sustain naïve mouse embryonic stem cell pluripotency and promote primordial germ cell differentiation. This observation together with other studies provides intriguing possibilities for stabilizing ephemeral embryonic cell states and enhancing desired fate transitions through specific metabolite manipulations. (Source: EMBO Journal)
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Lu, V., Teitell, M. A. Tags: Development & Differentiation, Metabolism, Stem Cells News [amp ] Views Source Type: research
A common molecular logic determines embryonic stem cell self-renewal and reprogramming
During differentiation and reprogramming, new cell identities are generated by reconfiguration of gene regulatory networks. Here, we combined automated formal reasoning with experimentation to expose the logic of network activation during induction of naïve pluripotency. We find that a Boolean network architecture defined for maintenance of naïve state embryonic stem cells (ESC) also explains transcription factor behaviour and potency during resetting from primed pluripotency. Computationally identified gene activation trajectories were experimentally substantiated at single-cell resolution by RT–qPCR...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Dunn, S.-J., Li, M. A., Carbognin, E., Smith, A., Martello, G. Tags: Stem Cells, Systems & Computational Biology, Transcription Resource Source Type: research
EGR2 phosphatase regulates OST1 kinase activity and freezing tolerance in Arabidopsis
This study thus unravels a molecular mechanism underlying cold activation of OST1 by membrane-localized EGR2 and suggests that a myristoyl switch on EGR2 helps plants to adapt to cold stress. (Source: EMBO Journal)
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Ding, Y., Lv, J., Shi, Y., Gao, J., Hua, J., Song, C., Gong, Z., Yang, S. Tags: Plant Biology, Post-translational Modifications, Proteolysis & Proteomics, Signal Transduction Articles Source Type: research
Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy
As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty a...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Rashid, T., Nemazanyy, I., Paolini, C., Tatsuta, T., Crespin, P., de Villeneuve, D., Brodesser, S., Benit, P., Rustin, P., Baraibar, M. A., Agbulut, O., Olivier, A., Protasi, F., Langer, T., Chrast, R., de Lonlay, P., de Foucauld, H., Blaauw, B., Pende, M Tags: Metabolism, Molecular Biology of Disease, Protein Biosynthesis & Quality Control Articles Source Type: research
Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and {beta}1-integrin
Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post-synaptically silent, suggesting that completion of early synaptogenesis may require a two-step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally-a...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Fossati, G., Pozzi, D., Canzi, A., Mirabella, F., Valentino, S., Morini, R., Ghirardini, E., Filipello, F., Moretti, M., Gotti, C., Annis, D. S., Mosher, D. F., Garlanda, C., Bottazzi, B., Taraboletti, G., Mantovani, A., Matteoli, M., Menna, E. Tags: Neuroscience Articles Source Type: research
Metabolic regulation of pluripotency and germ cell fate through {alpha}-ketoglutarate
An intricate link is becoming apparent between metabolism and cellular identities. Here, we explore the basis for such a link in an in vitro model for early mouse embryonic development: from naïve pluripotency to the specification of primordial germ cells (PGCs). Using single-cell RNA-seq with statistical modelling and modulation of energy metabolism, we demonstrate a functional role for oxidative mitochondrial metabolism in naïve pluripotency. We link mitochondrial tricarboxylic acid cycle activity to IDH2-mediated production of alpha-ketoglutarate and through it, the activity of key epigenetic regula...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Tischler, J., Gruhn, W. H., Reid, J., Allgeyer, E., Buettner, F., Marr, C., Theis, F., Simons, B. D., Wernisch, L., Surani, M. A. Tags: Development & Differentiation, Metabolism, Stem Cells Articles Source Type: research
Loss of VGLL4 suppresses tumor PD-L1 expression and immune evasion
Targeting immune checkpoints, such as PD-L1 and its receptor PD-1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD-L1 and PD-1 will improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP-induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti-tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell-mediated tumor regression in murine syngeneic models. VGLL4...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Wu, A., Wu, Q., Deng, Y., Liu, Y., Lu, J., Liu, L., Li, X., Liao, C., Zhao, B., Song, H. Tags: Cancer, Immunology Articles Source Type: research
SUMOylation coordinates BERosome assembly in active DNA demethylation during cell differentiation
During active DNA demethylation, 5-methylcytosine (5mC) is oxidized by TET proteins to 5-formyl-/5-carboxylcytosine (5fC/5caC) for replacement by unmethylated C by TDG-initiated DNA base excision repair (BER). Base excision generates fragile abasic sites (AP-sites) in DNA and has to be coordinated with subsequent repair steps to limit accumulation of genome destabilizing secondary DNA lesions. Here, we show that 5fC/5caC is generated at a high rate in genomes of differentiating mouse embryonic stem cells and that SUMOylation and the BER protein XRCC1 play critical roles in orchestrating TDG-initiated BER of these lesions. ...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Steinacher, R., Barekati, Z., Botev, P., Kusnierczyk, A., Slupphaug, G., Schär, P. Tags: Development & Differentiation, DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Loss of T-bet confers survival advantage to influenza-bacterial superinfection
The transcription factor, T-bet, regulates type 1 inflammatory responses against a range of infections. Here, we demonstrate a previously unaddressed role of T-bet, to influenza virus and bacterial superinfection. Interestingly, we found that T-bet deficiency did not adversely affect the efficacy of viral clearance or recovery compared to wild-type hosts. Instead, increased infiltration of neutrophils and production of Th17 cytokines (IL-17 and IL-22), in lungs of influenza virus-infected T-bet–/– mice, were correlated with survival advantage against subsequent infection by Streptococcus pneumoniae. Neutralizat...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Er, J. Z., Koean, R. A. G., Ding, J. L. Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
The kinetochore module Okp1CENP-Q/Ame1CENP-U is a reader for N-terminal modifications on the centromeric histone Cse4CENP-A
Kinetochores are supramolecular assemblies that link centromeres to microtubules for sister chromatid segregation in mitosis. For this, the inner kinetochore CCAN/Ctf19 complex binds to centromeric chromatin containing the histone variant CENP-A, but whether the interaction of kinetochore components to centromeric nucleosomes is regulated by posttranslational modifications is unknown. Here, we investigated how methylation of arginine 37 (R37Me) and acetylation of lysine 49 (K49Ac) on the CENP-A homolog Cse4 from Saccharomyces cerevisiae regulate molecular interactions at the inner kinetochore. Importantly, we found that th...
Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Anedchenko, E. A., Samel-Pommerencke, A., Tran Nguyen, T. M., Shahnejat-Bushehri, S., Pöpsel, J., Lauster, D., Herrmann, A., Rappsilber, J., Cuomo, A., Bonaldi, T., Ehrenhofer-Murray, A. E. Tags: Cell Cycle, Chromatin, Epigenetics, Genomics & Functional Genomics, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Open Access--or Open Science?
Open Access mandates in Europe raise the question if the priority is to reduce publishing costs, or the overdue conversion to Open Science communication. At risk are not only high-quality journals, but also community institutions and international research collaboration. (Source: EMBO Journal)
Source: EMBO Journal - December 14, 2018 Category: Molecular Biology Authors: Pulverer, B. Tags: Editorial Source Type: research
Optimized Chronos sets the clock for optogenetic hearing restoration
The coming of age of optogenetics has motivated the development of clinical applications. Improved hearing restoration by optical cochlear implants is one such promising development. However, slow closing of light-gated ion channels has remained an obstacle for achieving the high temporal fidelity required for optogenetic coding. In a study published in this issue, Keppeler et al demonstrate that optimized trafficking of the fast channelrhodopsin Chronos enables auditory nerve fibers to fire in response to light at near physiological rates. (Source: EMBO Journal)
Source: EMBO Journal - December 14, 2018 Category: Molecular Biology Authors: Ronzitti, E., Zampini, V., Emiliani, V. Tags: Neuroscience News [amp ] Views Source Type: research
More than just an I{kappa}B kinase: the IKK complex coordinates mRNA stability and transcription
The IB kinase (IKK) complex is best known as the core regulator of NF-B signalling. Recent work from Mikuda et al reveals a new and unexpected function for IKK in the regulation of mRNA stability. Through interacting with and phosphorylating EDC4, a key component of the mRNA decapping complex, IKK regulates P-body formation and the stability of numerous mRNAs, including many encoding inflammatory cytokines. Activation of IKK can therefore be more generally thought of as programming the cellular response to stress and infection through both mRNA stability and transcription. (Source: EMBO Journal)
Source: EMBO Journal - December 14, 2018 Category: Molecular Biology Authors: Perkins, N. D. Tags: Immunology, RNA Biology, Signal Transduction News [amp ] Views Source Type: research
A new consensus for evaluating CDKL5/STK9-dependent signalling mechanisms
Mutation or inactivation of CDKL5 kinase is associated with a human neurodevelopmental condition commonly referred to as CDKL5 deficiency disorder.§ Two recent phosphoproteomics studies identify the first physiological substrates of mammalian CDKL5 and evaluate functional consequences of their phosphorylation and its loss in cells lacking functional CDKL5, highlighting potential roles for this kinase in regulating neuronal microtubule dynamics. (Source: EMBO Journal)
Source: EMBO Journal - December 14, 2018 Category: Molecular Biology Authors: Eyers, P. A. Tags: Cell Adhesion, Polarity & Cytoskeleton, Genetics, Gene Therapy & Genetic Disease, Post-translational Modifications, Proteolysis & Proteomics News [amp ] Views Source Type: research
